ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.6007-5A>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_001042492.3(NF1):c.6007-5A>G
Variation ID: 359 Accession: VCV000000359.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q11.2 17: 31336328 (GRCh38) [ NCBI UCSC ] 17: 29663346 (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 20, 2024 Apr 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042492.3:c.6007-5A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_000267.3:c.5944-5A>G intron variant NC_000017.11:g.31336328A>G NC_000017.10:g.29663346A>G NG_009018.1:g.246352A>G LRG_214:g.246352A>G LRG_214t1:c.5944-5A>G - Protein change
- Other names
- IVS31AS, A-G, -5
- Canonical SPDI
- NC_000017.11:31336327: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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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
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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NF1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
13569 | 13970 |
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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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Apr 25, 2023 | RCV000000387.23 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2001 | RCV000000388.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2020 | RCV001582455.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2021 | RCV002316183.8 |
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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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782069.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Jan 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Medical Genomics Laboratory, Department of Genetics UAB
Accession: SCV001167431.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
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Pathogenic
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV001479134.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
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Pathogenic
(Oct 22, 2020)
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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: SCV001819650.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Non-canonical splice site variant demonstrated to result in loss-of-function (Kaufmann 2001, Pros 2008, Xu 2014, Giugliano 2019, Wimmer 2020); In silico analysis supports a deleterious … (more)
Non-canonical splice site variant demonstrated to result in loss-of-function (Kaufmann 2001, Pros 2008, Xu 2014, Giugliano 2019, Wimmer 2020); In silico analysis supports a deleterious effect on splicing; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31370276, 19221814, 24789688, 18546366, 32126153, 11704931, 10712197, 14569132, 7981692) (less)
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Pathogenic
(Jan 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000670372.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.5944-5A>G intronic pathogenic mutation results from an A to G substitution 5 nucleotides upstream from coding exon 40 in the NF1 gene. This mutation … (more)
The c.5944-5A>G intronic pathogenic mutation results from an A to G substitution 5 nucleotides upstream from coding exon 40 in the NF1 gene. This mutation has been reported in several individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (Ainsworth P et al. Hum Mol Genet, 1994 Jul;3:1179-81; Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Kaufmann D et al. Am J Hum Genet, 2001 Dec;69:1395-400; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60). In addition, this alteration results in the insertion of four nucleotides between NF1 exons 39 and 40, leading to creation of a premature stop codon (Ainsworth P et al. Hum Mol Genet, 1994 Jul;3:1179-81; Kaufmann D et al. Am J Hum Genet, 2001 Dec;69:1395-400; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002560169.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
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Pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259361.7
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 7981692, 11704931). The resulting … (more)
Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 7981692, 11704931). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 359). This variant has been observed in individuals with neurofibromatosis type 1 and/or NF1-related conditions (PMID: 7981692, 10712197, 11704931, 18546366, 24789688; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 39 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. (less)
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Pathogenic
(Dec 01, 2001)
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no assertion criteria provided
Method: literature only
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NEUROFIBROMATOSIS, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020531.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a patient with neurofibromatosis type I (NF1; 162200), Fahsold et al. (2000) identified an A-to-G transition in the NF1 gene splice acceptor site of … (more)
In a patient with neurofibromatosis type I (NF1; 162200), Fahsold et al. (2000) identified an A-to-G transition in the NF1 gene splice acceptor site of exon 31 (IVS31-5A-G), resulting in the addition of 4 bases to exon 32 and a premature stop codon at amino acid 1995. In affected members of a family with spinal neurofibromatosis without cafe-au-lait macules (162210), Kaufmann et al. (2001) identified the exon 31 splice site mutation. Noting that the same mutation had been reported in a patient with classic NF1, the authors concluded that a modifying gene may compensate for some of the effects of neurofibromin deficiency. The splice site NF1 mutation resulted in instability of the neurofibromin protein. (less)
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Pathogenic
(Dec 01, 2001)
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no assertion criteria provided
Method: literature only
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NEUROFIBROMATOSIS, FAMILIAL SPINAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020532.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a patient with neurofibromatosis type I (NF1; 162200), Fahsold et al. (2000) identified an A-to-G transition in the NF1 gene splice acceptor site of … (more)
In a patient with neurofibromatosis type I (NF1; 162200), Fahsold et al. (2000) identified an A-to-G transition in the NF1 gene splice acceptor site of exon 31 (IVS31-5A-G), resulting in the addition of 4 bases to exon 32 and a premature stop codon at amino acid 1995. In affected members of a family with spinal neurofibromatosis without cafe-au-lait macules (162210), Kaufmann et al. (2001) identified the exon 31 splice site mutation. Noting that the same mutation had been reported in a patient with classic NF1, the authors concluded that a modifying gene may compensate for some of the effects of neurofibromin deficiency. The splice site NF1 mutation resulted in instability of the neurofibromin protein. (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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AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides. | Wimmer K | Human mutation | 2020 | PMID: 32126153 |
Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. | Xu W | International journal of molecular medicine | 2014 | PMID: 24789688 |
Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. | Pros E | Human mutation | 2008 | PMID: 18546366 |
Spinal neurofibromatosis without café-au-lait macules in two families with null mutations of the NF1 gene. | Kaufmann D | American journal of human genetics | 2001 | PMID: 11704931 |
Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. | Fahsold R | American journal of human genetics | 2000 | PMID: 10712197 |
Characterization of an intron 31 splice junction mutation in the neurofibromatosis type 1 (NF1) gene. | Ainsworth P | Human molecular genetics | 1994 | PMID: 7981692 |
Text-mined citations for rs267606604 ...
HelpRecord last updated Mar 23, 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.