dbSNP rs775387808: SLC45A2:p.Gly89AspfsTer24 (chr5-33984319-CG-C) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_016180.5(SLC45A2):c.264delC(p.Gly89AspfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SLC45A2
NM_016180.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.0810

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-33984319-CG-C is Pathogenic according to our data. Variant chr5-33984319-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-33984319-CG-C is described in Lovd as [Pathogenic]. Variant chr5-33984319-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A2	NM_016180.5 link	c.264delC	p.Gly89AspfsTer24	frameshift_variant	Exon 1 of 7	ENST00000296589.9	NP_057264.4	Q9UMX9-1A0A076YGN1A0A076YIB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000296589.9 link	c.264delC	p.Gly89AspfsTer24	frameshift_variant	Exon 1 of 7	1	NM_016180.5	ENSP00000296589.4		Q9UMX9-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000996

AC:

AN:

251016

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000235

AC:

344

AN:

1461780

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

163

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000288

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000226

Hom.:

Bravo

AF:

0.0000945

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oculocutaneous albinism type 4

Pathogenic:3

Aug 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC45A2 c.264delC (p.Gly89AspfsTer24) variant has been reported in at least two studies and identified in a total of three individuals, including two homozygous siblings with oculocutaneous albinism (OCA) type 4 and C6 deficiency, and one compound heterozygous individual with OCA4 (Ikinciogullari et al. 2005; Wilk et al. 2014). The siblings also carried a homozygous nonsense variant in the C6 gene (Ikinciogullari et al. 2005). Control data are unavailable for this variant, which is reported at a frequency of 0.000293 in the African population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of a frameshift variant, the p.Gly89AspfsTer24 variant is classified as likely pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 13, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:3

Apr 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34174832, 34078970, 17767372, 26053207, 24845642, 31589614, 32411182, 15565285) -

Oct 24, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly89Aspfs*24) in the SLC45A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC45A2 are known to be pathogenic (PMID: 21458243, 26573111). This variant is present in population databases (rs775387808, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 15565285, 28976636). ClinVar contains an entry for this variant (Variation ID: 242518). For these reasons, this variant has been classified as Pathogenic. -

SKIN/HAIR/EYE PIGMENTATION 5, BLACK/NONBLACK HAIR

Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SLC45A2-related disorder

Pathogenic:1

Aug 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC45A2 c.264delC variant is predicted to result in a frameshift and premature protein termination (p.Gly89Aspfs*24). This variant has been reported as causative for autosomal recessive oculocutaneous albinism (see for examples Wilk et al. 2014. PubMed ID: 24845642; Kruijt et al. 2021. PubMed ID: 34078970). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SLC45A2 are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/242518). Given the evidence, we interpret this variant as pathogenic. -

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