rs780269002
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_032444.4(SLX4):c.1945G>A(p.Gly649Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_032444.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000718 AC: 18AN: 250664Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135626
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461784Hom.: 0 Cov.: 32 AF XY: 0.0000591 AC XY: 43AN XY: 727192
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74314
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: SLX4 c.1945G>A (p.Gly649Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250664 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLX4 causing Fanconi Anemia, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1945G>A in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 526415). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Fanconi anemia Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 649 of the SLX4 protein (p.Gly649Ser). This variant is present in population databases (rs780269002, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SLX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 526415). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 P Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at