ClinVar Genomic variation as it relates to human health
NM_000135.4(FANCA):c.3412C>G (p.Leu1138Val)
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_000135.4(FANCA):c.3412C>G (p.Leu1138Val)
Variation ID: 134265 Accession: VCV000134265.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 89746685 (GRCh38) [ NCBI UCSC ] 16: 89813093 (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 Jun 9, 2014 May 12, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000135.4:c.3412C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000126.2:p.Leu1138Val missense NM_001286167.3:c.3412C>G NP_001273096.1:p.Leu1138Val missense NC_000016.10:g.89746685G>C NC_000016.9:g.89813093G>C NG_011706.1:g.74973C>G LRG_495:g.74973C>G LRG_495t1:c.3412C>G - Protein change
- L1138V
- Other names
- -
- Canonical SPDI
- NC_000016.10:89746684:G:C
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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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0.00180 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00029
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD) 0.00041
The Genome Aggregation Database (gnomAD), exomes 0.00150
Exome Aggregation Consortium (ExAC) 0.00153
1000 Genomes Project 30x 0.00156
1000 Genomes Project 0.00180
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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FANCA | - | - |
GRCh38 GRCh37 |
4075 | 5199 |
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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Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2022 | RCV000120938.9 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000228134.16 | |
Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000674808.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 1, 2024 | RCV001311466.18 |
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 benign
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804219.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000283562.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Likely benign
(May 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800208.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000399826.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Likely benign
(Feb 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002068419.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500151.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: FANCA c.3412C>G (p.Leu1138Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: FANCA c.3412C>G (p.Leu1138Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251228 control chromosomes, predominantly at a frequency of 0.0093 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Jul 01, 2021)
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criteria provided, single submitter
Method: curation
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535004.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jan 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501639.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
FANCA: BS2
Number of individuals with the variant: 6
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552187.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The FANCA p.Leu1138Val variant was identified in 1 of 90 proband chromosomes (frequency: 0.011) from individuals with breast cancer (Jalkh_2017_PMID:28202063). The variant was identified in … (more)
The FANCA p.Leu1138Val variant was identified in 1 of 90 proband chromosomes (frequency: 0.011) from individuals with breast cancer (Jalkh_2017_PMID:28202063). The variant was identified in dbSNP (ID: rs138417003) and ClinVar (classified as benign by Invitae, as likely benign by Counsyl and as uncertain significance by Illumina). The variant was identified in control databases in 390 of 282634 chromosomes (5 homozygous) at a frequency of 0.00138 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 284 of 30614 chromosomes (freq: 0.009277), Other in 13 of 7222 chromosomes (freq: 0.0018), Latino in 30 of 35420 chromosomes (freq: 0.000847), African in 18 of 24960 chromosomes (freq: 0.000721) and European (non-Finnish) in 45 of 129076 chromosomes (freq: 0.000349), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Leu1138 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
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Benign
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Fanconi anemia, group A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462878.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085106.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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
HelpText-mined citations for rs138417003 ...
HelpRecord last updated May 12, 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.