rs149551759
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000135.4(FANCA):c.1340C>T(p.Ser447Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S447S) has been classified as Likely benign.
Frequency
Consequence
NM_000135.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.1340C>T | p.Ser447Leu | missense_variant | 14/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.1340C>T | p.Ser447Leu | missense_variant | 14/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.1340C>T | p.Ser447Leu | missense_variant | 14/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000379 AC: 95AN: 250708Hom.: 0 AF XY: 0.000288 AC XY: 39AN XY: 135580
GnomAD4 exome AF: 0.000322 AC: 470AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.000319 AC XY: 232AN XY: 727152
GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74374
ClinVar
Submissions by phenotype
Fanconi anemia complementation group A Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 08, 2022 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported with another FANCA variant in an individual who also carried two variants in the SBDS gene (Churpek et al., 2015).; This variant is associated with the following publications: (PMID: 26492932) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 30, 2022 | The frequency of this variant in the general population, 0.00064 (83/128734 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with epithelial ovarian cancer (PMID: 32546565 (2021)), Myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) (PMID: 26492932 (2015)), and healthy individuals (PMID: 32546565 (2021)). Functional studies assessing the variant's role within the Fanconi Anemia pathway report no impact to protein binding (PMID: 28215707 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Fanconi anemia Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 04, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
FANCA-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 19, 2023 | The FANCA c.1340C>T variant is predicted to result in the amino acid substitution p.Ser447Leu. This variant was reported in the compound heterozygous state with a second FANCA variant (c.3349-3C>T) in an individual with myelodysplastic syndrome / acute myeloid leukemia; however, this individual also had two compound heterozygous variants in the SBDS gene (Churpek et al. 2015. PubMed ID: 26492932). This variant is reported in 0.088% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89857830-G-A) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/237034/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at