16-89805328-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000135.4(FANCA):c.661A>G(p.Met221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.661A>G | p.Met221Val | missense_variant | Exon 7 of 43 | ENST00000389301.8 | NP_000126.2 | |
FANCA | NM_001286167.3 | c.661A>G | p.Met221Val | missense_variant | Exon 7 of 43 | NP_001273096.1 | ||
FANCA | NM_001018112.3 | c.661A>G | p.Met221Val | missense_variant | Exon 7 of 11 | NP_001018122.1 | ||
FANCA | NM_001351830.2 | c.565A>G | p.Met189Val | missense_variant | Exon 6 of 10 | NP_001338759.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249370Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 134980
GnomAD4 exome AF: 0.000107 AC: 157AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87AN XY: 727206
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74302
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
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This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 221 of the FANCA protein (p.Met221Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with pancreatic cancer (PMID: 15591268). ClinVar contains an entry for this variant (Variation ID: 408195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA protein function. 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
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not provided Uncertain:2
The FANCA c.661A>G (p.Met221Val) variant has been reported in the published literature in an individual with pancreatic cancer (PMID: 15591268 (2004)). The frequency of this variant in the general population, 0.000079 (10/127146 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer (Rogers 2004); This variant is associated with the following publications: (PMID: 15591268) -
not specified Uncertain:1
Variant summary: FANCA c.661A>G (p.Met221Val) results in a conservative amino acid change located in the Fanconi anaemia group A protein, N-terminal domain (IPR031729) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249370 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.661A>G has been reported in the literature in an individual affected with Pancreatic cancer (Rogers_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15591268). ClinVar contains an entry for this variant (Variation ID: 408195). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at