rs763833617
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_032444.4(SLX4):c.1405C>T(p.Pro469Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P469A) has been classified 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLX4 | NM_032444.4 | c.1405C>T | p.Pro469Ser | missense_variant | 7/15 | ENST00000294008.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLX4 | ENST00000294008.4 | c.1405C>T | p.Pro469Ser | missense_variant | 7/15 | 5 | NM_032444.4 | P1 | |
SLX4 | ENST00000466154.5 | n.2626C>T | non_coding_transcript_exon_variant | 5/7 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250512Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135648
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461758Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727182
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74326
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 04, 2021 | This sequence change does not appear to have been previously described in patients with SLX4-related disorders and has been described in the gnomAD database with a low population frequency of 0.0024% (dbSNP rs763833617). The p.Pro469Ser change affects a highly 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.Pro469Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro469Ser change remains unknown at this time. - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 22, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 469 of the SLX4 protein (p.Pro469Ser). This variant is present in population databases (rs763833617, 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: 1337807). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 15, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at