rs753485165

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.58

Variant links:

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]

SLC45A2 links:

Genome browser will be placed here

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
SLC45A2	NM_016180.5 linkuse as main transcript	c.1076_1077del	p.Glu359ValfsTer85	frameshift_variant	5/7	ENST00000296589.9
SLC45A2	NM_001012509.4 linkuse as main transcript	c.1076_1077del	p.Glu359ValfsTer85	frameshift_variant	5/6
SLC45A2	XM_047417259.1 linkuse as main transcript	c.836_837del	p.Glu279ValfsTer85	frameshift_variant	5/7
SLC45A2	NM_001297417.4 linkuse as main transcript	c.18_19del		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC45A2	ENST00000296589.9 linkuse as main transcript	c.1076_1077del	p.Glu359ValfsTer85	frameshift_variant	5/7	1	NM_016180.5	P1	Q9UMX9-1
SLC45A2	ENST00000382102.7 linkuse as main transcript	c.1076_1077del	p.Glu359ValfsTer85	frameshift_variant	5/6	1			Q9UMX9-4
SLC45A2	ENST00000509381.1 linkuse as main transcript	c.18_19del		3_prime_UTR_variant	4/4	1
SLC45A2	ENST00000510600.1 linkuse as main transcript	c.551_552del	p.Glu184ValfsTer?	frameshift_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251474

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461884

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000302

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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over