chr5-33944709-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3PP5
The NM_016180.5(SLC45A2):c.1532C>T(p.Ala511Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,090 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A511E) has been classified as Pathogenic.
Frequency
Consequence
NM_016180.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC45A2 | NM_016180.5 | c.1532C>T | p.Ala511Val | missense_variant | 7/7 | ENST00000296589.9 | |
SLC45A2 | XM_047417259.1 | c.1292C>T | p.Ala431Val | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC45A2 | ENST00000296589.9 | c.1532C>T | p.Ala511Val | missense_variant | 7/7 | 1 | NM_016180.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251330Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135854
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 12, 2020 | The sequence change, c.1532C>T, in exon 7 results in an amino acid change, p.Ala511Val. The p.Ala511Val change affects a highly conserved amino acid residue located in a domain of the SLC45A2 protein that is known to be functional. The p.Ala511Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Mutation Taster, REVEL). This particular amino acid change has been described in Pakistani consanguineous families with oculocutaneous albinism in the homozygous state (PMIDs: 28266639, 30868578). This sequence change has been described in the gnomAD database in three heterozygous individuals which corresponds to a population frequency of 0.0011% (dbSNP rs748872789); however, it has not been observed in homozygous state in any individuals. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 05, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 511 of the SLC45A2 protein (p.Ala511Val). 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 clinical features of oculocutaneous albinism (PMID: 30868578). ClinVar contains an entry for this variant (Variation ID: 617813). 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"). This variant disrupts the p.Ala511 amino acid residue in SLC45A2. Other variant(s) that disrupt this residue have been observed in individuals with SLC45A2-related conditions (PMID: 18821858), which suggests that this may be a clinically significant amino acid residue. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2021 | This variant is associated with the following publications: (PMID: 31589614, 23190901, 32221475, 31229681, 30868578, 28266639) - |
Nonsyndromic Oculocutaneous Albinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Mar 07, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at