rs377440877
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_032444.4(SLX4):c.1499C>T(p.Thr500Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251438Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135904
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.0000591 AC XY: 43AN XY: 727232
GnomAD4 genome AF: 0.000171 AC: 26AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74306
ClinVar
Submissions by phenotype
Fanconi anemia complementation group P Uncertain:2
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not specified Uncertain:1
DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.1499C>T, in exon 7 that results in an amino acid change, p.Thr500Met. This sequence change has been described in the gnomAD database with a frequency of 0.028% in the African/African American subpopulation (dbSNP rs377440877). The p.Thr500Met change affects a moderately conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr500Met substitution. This sequence change does not appear to have been previously described in individuals with SLX4-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr500Met change remains unknown at this time. -
Fanconi anemia Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 500 of the SLX4 protein (p.Thr500Met). This variant is present in population databases (rs377440877, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 30613976). ClinVar contains an entry for this variant (Variation ID: 526360). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at