chr15-48134940-T-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_205850.3(SLC24A5):c.546T>A(p.Ser182Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S182G) has been classified as Uncertain significance.
Frequency
Consequence
NM_205850.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC24A5 | NM_205850.3 | c.546T>A | p.Ser182Arg | missense_variant | 5/9 | ENST00000341459.8 | |
MYEF2 | NM_016132.5 | c.*7968A>T | 3_prime_UTR_variant | 17/17 | ENST00000324324.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC24A5 | ENST00000341459.8 | c.546T>A | p.Ser182Arg | missense_variant | 5/9 | 1 | NM_205850.3 | P1 | |
SLC24A5 | ENST00000449382.2 | c.366T>A | p.Ser122Arg | missense_variant | 4/8 | 1 | |||
MYEF2 | ENST00000324324.12 | c.*7968A>T | 3_prime_UTR_variant | 17/17 | 1 | NM_016132.5 | P4 | ||
SLC24A5 | ENST00000463289.1 | n.306T>A | non_coding_transcript_exon_variant | 4/5 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 182 of the SLC24A5 protein (p.Ser182Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculocutaneous albinism type VI (PMID: 23985994, 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372809). 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 expected to disrupt SLC24A5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC24A5 function (PMID: 27129268, 32274888). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2016 | The S182R variant in the SLC24A5 gene has been reported previously in the homozygous state in an individual of Syrian ancestry with oculocutaneous albinism (Morice-Picard et al., 2014). The S182R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S182R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The S182R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SLC24A5: PM2, PM3, PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at