rs587778324
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000135.4(FANCA):c.754_755delGAinsAG(p.Asp252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252G) has been classified as Likely benign.
Frequency
Consequence
NM_000135.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.754_755delGAinsAG | p.Asp252Ser | missense_variant | ENST00000389301.8 | NP_000126.2 | ||
FANCA | NM_001286167.3 | c.754_755delGAinsAG | p.Asp252Ser | missense_variant | NP_001273096.1 | |||
FANCA | NM_001018112.3 | c.754_755delGAinsAG | p.Asp252Ser | missense_variant | NP_001018122.1 | |||
FANCA | NM_001351830.2 | c.658_659delGAinsAG | p.Asp220Ser | missense_variant | NP_001338759.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.754_755delGAinsAG | p.Asp252Ser | missense_variant | 1 | NM_000135.4 | ENSP00000373952.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 01, 2022 | PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 04, 2023 | - - |
Fanconi anemia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 08, 2021 | The FANCA c.754_755delinsAG (p.Asp252Ser) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). In silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 08, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 252 of the FANCA protein (p.Asp252Ser). This variant is present in population databases (rs587778324, gnomAD 4%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 134291). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Fanconi anemia complementation group A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 30, 2023 | The FANCA c.754_755delinsAG (p.Asp252Ser) change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect of this variant on protein function, but these predictions have not been confirmed by functional studies. This variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at