ClinVar Genomic variation as it relates to human health
NM_002528.7(NTHL1):c.685+1G>A
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_002528.7(NTHL1):c.685+1G>A
Variation ID: 218092 Accession: VCV000218092.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2043566 (GRCh38) [ NCBI UCSC ] 16: 2093567 (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 Aug 22, 2016 Feb 14, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002528.7:c.685+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001318193.2:c.514+1G>A splice donor NM_001318194.2:c.355+1G>A splice donor NC_000016.10:g.2043566C>T NC_000016.9:g.2093567C>T NG_008412.1:g.9301G>A LRG_1366:g.9301G>A LRG_1366t1:c.685+1G>A - Protein change
- Other names
- IVS4DS, G-A, +1
- Canonical SPDI
- NC_000016.10:2043565:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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NTHL1 | - | - |
GRCh38 GRCh37 |
1464 | 1570 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 5, 2023 | RCV000202319.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000807122.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2023 | RCV003352802.1 |
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
Help
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
Help
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
Help
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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Likely pathogenic
(Jan 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002808478.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004025961.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PVS1, PM2_SUP, PM3
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Pathogenic
(Aug 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004062637.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The c.709+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the NTHL1 gene. This mutation was … (more)
The c.709+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the NTHL1 gene. This mutation was confirmed in trans with another NTHL1 pathogenic variant (p.Q90*) in a patient affected with >30 colon polyps and multiple cancer diagnoses, including colon adenocarcinoma. RNA studies on this individual and her heterozygous daughter demonstrated abnormal splicing (Rivera B et al. N Engl J Med, 2015 Nov;373:1985-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Likely pathogenic
(Sep 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial adenomatous polyposis 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004188341.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
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Pathogenic
(Jan 27, 2024)
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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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Invitae
Accession: SCV000947161.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 4 of the NTHL1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 4 of the NTHL1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs372946560, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of NTHL1-related conditions (PMID: 26559593). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 218092). Studies have shown that disruption of this splice site results in multiple aberrant splice products and introduces a premature termination codon (PMID: 26559593). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 12, 2015)
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no assertion criteria provided
Method: literature only
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FAMILIAL ADENOMATOUS POLYPOSIS 3
Affected status: not provided
Allele origin:
unknown
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OMIM
Accession: SCV000257324.2
First in ClinVar: Nov 22, 2015 Last updated: Aug 22, 2016 |
Comment on evidence:
In a German woman with familial adenomatous polyposis-3 (FAP3; 616415) and multiple additional extracolonic neoplasms, Rivera et al. (2015) identified compound heterozygous mutations in the … (more)
In a German woman with familial adenomatous polyposis-3 (FAP3; 616415) and multiple additional extracolonic neoplasms, Rivera et al. (2015) identified compound heterozygous mutations in the NTHL1 gene: a c.709+1G-A transition in intron 4 (c.709+1G-A, NM_002528), resulting in a splice site defect that was detectable in patient cells, and Q90X (602656.0001). The patient developed colonic adenocarcinoma at age 41, and was later found to have bladder carcinoma, intradermal nevi, meningioma, multiple seborrheic keratoses, basal cell carcinoma, multiple colorectal adenomas, squamous cell carcinoma, and invasive ductal carcinoma. Six different tumors from the proband were found to carry somatic mutations in driver genes, such as FGFR3 (134934). She also had a family history of cancer. (less)
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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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Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors. | Rivera B | The New England journal of medicine | 2015 | PMID: 26559593 |
Text-mined citations for rs372946560 ...
HelpRecord last updated Feb 20, 2024
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.