rs200093209
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000135.4(FANCA):c.2856G>C(p.Gln952His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 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. Q952P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000135.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.2856G>C | p.Gln952His | missense_variant | 30/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.2856G>C | p.Gln952His | missense_variant | 30/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.2856G>C | p.Gln952His | missense_variant | 30/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251182Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135790
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461276Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 726936
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74352
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2019 | - - |
Fanconi anemia complementation group A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 03, 2022 | The FANCA c.4300G>A (p.Ala1434Thr) missense change has a maximum subpopulation frequency of 0.050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-89825110-C-G?dataset=gnomad_r2_1). Six of seven 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 assays. 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: BP4. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 11, 2023 | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0022 (23/10368 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Fanconi anemia Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at