rs753485165
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_016180.5(SLC45A2):c.1076_1077del(p.Glu359ValfsTer85) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,048 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 1 hom. )
Consequence
SLC45A2
NM_016180.5 frameshift
NM_016180.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.58
Genes affected
SLC45A2 (HGNC:16472): (solute carrier family 45 member 2) This gene encodes a transporter protein that mediates melanin synthesis. The protein is expressed in a high percentage of melanoma cell lines. Mutations in this gene are a cause of oculocutaneous albinism type 4, and polymorphisms in this gene are associated with variations in skin and hair color. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 5-33951632-ACT-A is Pathogenic according to our data. Variant chr5-33951632-ACT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 353216.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr5-33951632-ACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC45A2 | NM_016180.5 | c.1076_1077del | p.Glu359ValfsTer85 | frameshift_variant | 5/7 | ENST00000296589.9 | |
SLC45A2 | NM_001012509.4 | c.1076_1077del | p.Glu359ValfsTer85 | frameshift_variant | 5/6 | ||
SLC45A2 | XM_047417259.1 | c.836_837del | p.Glu279ValfsTer85 | frameshift_variant | 5/7 | ||
SLC45A2 | NM_001297417.4 | c.*18_*19del | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC45A2 | ENST00000296589.9 | c.1076_1077del | p.Glu359ValfsTer85 | frameshift_variant | 5/7 | 1 | NM_016180.5 | P1 | |
SLC45A2 | ENST00000382102.7 | c.1076_1077del | p.Glu359ValfsTer85 | frameshift_variant | 5/6 | 1 | |||
SLC45A2 | ENST00000509381.1 | c.*18_*19del | 3_prime_UTR_variant | 4/4 | 1 | ||||
SLC45A2 | ENST00000510600.1 | c.551_552del | p.Glu184ValfsTer? | frameshift_variant | 4/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251474Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135912
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461884Hom.: 1 AF XY: 0.0000179 AC XY: 13AN XY: 727246
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74324
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Oculocutaneous albinism type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 07, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Glu359Valfs*85) in the SLC45A2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 172 amino acid(s) of the SLC45A2 protein. This variant is present in population databases (rs753485165, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 18463683). This variant is also known as c.1074-1077delAG. This variant disrupts a region of the SLC45A2 protein in which other variant(s) (p.Pro419Leu) have been determined to be pathogenic (PMID: 19865097, 21287499, 28976636). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Oculocutaneous albinism Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.1076_1077delAG (p.Glu359ValfsTer85) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Glu359ValfsTer85 variant was identified in one study in a compound heterozygous state in one patient who was described as having a clinical diagnosis of oculocutaneous albinism type 1B and a molecular diagnosis of oculocutaneous albinism type 4 (Hutton & Spritz 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00045 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence and due to the potential impact of frameshift variants, the p.Glu359ValfsTer85 variant is classified as a variant of unknown significance but suspicious for pathogenicity for oculocutaneous albinism. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at