ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.3874-4522A>G
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.3874-4522A>G
Variation ID: 500071 Accession: VCV000500071.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117648320 (GRCh38) [ NCBI UCSC ] 7: 117288374 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 2, 2018 Jan 25, 2025 Jun 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.3874-4522A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000007.14:g.117648320A>G NC_000007.13:g.117288374A>G NG_016465.4:g.187537A>G LRG_663:g.187537A>G LRG_663t1:c.3874-4522A>G - Protein change
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- Other names
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- Canonical SPDI
- NC_000007.14:117648319:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CFTR | - | - |
GRCh38 GRCh37 |
3941 | 5359 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 2, 2024 | RCV000597152.35 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000665784.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2018 | RCV001009398.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2024 | RCV003471958.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2023 | RCV004530697.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2024 | RCV005044889.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 29, 2018)
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criteria provided, single submitter
Method: curation
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cystic fibrosis
CFTR-related disorders
Affected status: yes
Allele origin:
germline
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CFTR-France
Accession: SCV001169251.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
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Pathogenic
(Jul 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570339.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
CFTR c.3874-4522A>G has been identified in multiple individuals with features of cystic fibrosis including one who has a known CF-causing variant on the opposite chromosome. … (more)
CFTR c.3874-4522A>G has been identified in multiple individuals with features of cystic fibrosis including one who has a known CF-causing variant on the opposite chromosome. This CFTR variant has been reported in ClinVar (Variation ID: 500071), but is absent from a large population dataset. Functional studies demonstrate that this deep intronic variant creates a cryptic splice site that leads to aberrant splicing. We consider CFTR c.3874-4522A>G to be pathogenic. (less)
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Pathogenic
(Mar 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922695.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: CFTR c.3874-4522A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal … (more)
Variant summary: CFTR c.3874-4522A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3' acceptor site and one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence from sequencing RNA from compound heterozygous individuals with the variant, as well as a minigene assay, that shows this variant indeed affects mRNA splicing (Bergougnoux_2019). This study showed that the variant results in aberrant splicing which leads to the inclusion of a 125bp pseudo-exon, predicted to result in a premature stop codon, in 76% of RNA transcripts. The variant was absent in 31150 control chromosomes (gnomAD). c.3874-4522A>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with Cystic Fibrosis and CFTR-related disorders, including cases where it has been confirmed to be in trans with a pathogenic variant (e.g. Roth_2011, Bergougnoux_2019 Morris-Rosendahl_2020). These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=4)/likely pathogenic (n=1) or VUS (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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CFTR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119590.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CFTR c.3874-4522A>G variant is predicted to interfere with splicing. This variant, previously reported as c.4005+5727A>G, has been reported in patients with cystic fibrosis (Bonini … (more)
The CFTR c.3874-4522A>G variant is predicted to interfere with splicing. This variant, previously reported as c.4005+5727A>G, has been reported in patients with cystic fibrosis (Bonini et al. 2015. PubMed ID: 25569440; Roth et al. 2011. PubMed ID: 21909392; Ellingford et al. 2022. PubMed ID: 35850704). This variant was also described in ten additional individuals with various CFTR-related phenotypes ranging from male infertility to cystic fibrosis with pancreatic insufficiency (Bergougnoux et al. 2018. PubMed ID: 30389601) and was reported in another study in the compound heterozygous state in twelve patients with cystic fibrosis (Morris-Rosendahl et al. 2020. PubMed ID: 32017858). In vitro splicing analysis indicates that this change results in inclusion of 125 bp (Bergougnoux et al. 2018. PubMed ID: 30389601). In Clinvar, this variant has been listed from 'uncertain' to 'pathogenic' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/500071/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, we classify this variant as likely pathogenic. (less)
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Pathogenic
(Apr 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221694.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000024 (1/41384 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been … (more)
The frequency of this variant in the general population, 0.000024 (1/41384 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported to co-occur with other pathogenic CFTR variants and has been associated with various phenotypes including male infertility and cystic fibrosis with pancreatic insufficiency (PMID: 30389601 (2019), 21909392 (2011), CFTR-France https://cftr.iurc.montp.inserm.fr/). In addition, a splicing analysis performed using cells taken from multiple individuals with cystic fibrosis has found that this variant results in aberrant splicing (PMID: 30389601 (2019)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001589605.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 23 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. … (more)
This sequence change falls in intron 23 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cystic fibrosis (PMID: 21909392, 30389601). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 4005+5727A>G. ClinVar contains an entry for this variant (Variation ID: 500071). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30389601). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562671.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CFTR c.3874-4522A>G variant (rs895394181) is reported in the literature in multiple individuals affected with cystic fibrosis and CFTR related disorders (Bergougnoux 2019, Roth 2011, … (more)
The CFTR c.3874-4522A>G variant (rs895394181) is reported in the literature in multiple individuals affected with cystic fibrosis and CFTR related disorders (Bergougnoux 2019, Roth 2011, Shen 2022, Su 2023). This variant is also reported in ClinVar (Variation ID: 500071) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. A minigene assay found this variant affects mRNA splicing resulting in the inclusion of a 125bp pseudo-exon that is predicted to result in a premature stop codon in a majority of RNA transcripts (Bergougnoux 2019). Based on available information, this variant is considered to be likely pathogenic. References: Bergougnoux A et al. Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene. J Cyst Fibros. 2019 Jul;18(4):468-475. PMID: 30389601. Roth EK et al. The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. PLoS One. 2011;6(8):e24445. PMID: 21909392. Shen Y et al. Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China. J Med Genet. 2022 Jul 20;60(3):310–5. PMID: 35858753. Su Y et al. Case report of a pediatric Chinese cystic fibrosis patient with the c.1521_1523delCTT/c.3874-4522A>G genotype. Pediatr Pulmonol. 2023 Feb;58(2):556-558. PMID: 36349818. (less)
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Likely pathogenic
(Sep 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002622436.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.3874-4522A>G intronic variant (also known as c.4005+5727A>G) results from an A to G substitution 4522 nucleotides before coding exon 24 in the CFTR gene. … (more)
The c.3874-4522A>G intronic variant (also known as c.4005+5727A>G) results from an A to G substitution 4522 nucleotides before coding exon 24 in the CFTR gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in trans with a pathogenic CFTR mutation in an individual with classic cystic fibrosis (CF), and it has been observed in individuals with CFTR-related disorders, some of whom have other CFTR variants of undetermined phase (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475; Roth EK et al. PLoS One, 2011 Aug;6:e24445). One experimental study shows that this variant disrupts mRNA splicing; however, the variant's effect on splicing is incomplete (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475) This nucleotide position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis with or without elevated sweat chloride 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213281.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(May 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001988688.5
First in ClinVar: Nov 06, 2021 Last updated: Sep 16, 2024 |
Comment:
Observed multiple times with a second CFTR causing variant in patients with cystic fibrosis or CFTR-related disorders, but it is not known whether the variants … (more)
Observed multiple times with a second CFTR causing variant in patients with cystic fibrosis or CFTR-related disorders, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 21909392, 28603918); No data available from control populations to assess the frequency of this variant; Also known as 4005 + 5727A>G; This variant is associated with the following publications: (PMID: 25569440, 30389601, 31845523, 32017858, 38246579, 37867076, 35850704, 36349818, 35858753, 34663891, 37445855, 33020115, 37477516, 21909392, 28603918) (less)
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Pathogenic
(Dec 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062782.21
First in ClinVar: Jan 29, 2022 Last updated: Dec 22, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Fulgent Genetics, Fulgent Genetics
Accession: SCV005666428.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
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Uncertain significance
(Feb 28, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000789957.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Jan 23, 2017)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000705855.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Intestinal current measurement and nasal potential difference to make a diagnosis of cases with inconclusive CFTR genetics and sweat test. | Minso R | BMJ open respiratory research | 2020 | PMID: 33020115 |
Whole-Gene Sequencing of CFTR Reveals a High Prevalence of the Intronic Variant c.3874-4522A>G in Cystic Fibrosis. | Morris-Rosendahl DJ | American journal of respiratory and critical care medicine | 2020 | PMID: 32017858 |
Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene. | Bergougnoux A | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2019 | PMID: 30389601 |
Small-scale high-throughput sequencing-based identification of new therapeutic tools in cystic fibrosis. | Bonini J | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25569440 |
The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. | Roth EK | PloS one | 2011 | PMID: 21909392 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
Text-mined citations for rs895394181 ...
HelpRecord last updated Feb 01, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.