Variant chr5-33951588-CA-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_016180.5(SLC45A2):c.1121delT(p.Leu374fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC45A2
NM_016180.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.03

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-33951588-CA-C is Pathogenic according to our data. Variant chr5-33951588-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 4506.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC45A2	NM_016180.5 linkuse as main transcript	c.1121delT	p.Leu374fs	frameshift_variant	5/7	ENST00000296589.9	NP_057264.4	Q9UMX9-1A0A076YGN1A0A076YIB8
SLC45A2	NM_001012509.4 linkuse as main transcript	c.1121delT	p.Leu374fs	frameshift_variant	5/6		NP_001012527.2	Q9UMX9-4
SLC45A2	XM_047417259.1 linkuse as main transcript	c.881delT	p.Leu294fs	frameshift_variant	5/7		XP_047273215.1
SLC45A2	NM_001297417.4 linkuse as main transcript	c.*63delT		3_prime_UTR_variant	4/4		NP_001284346.2	Q9UMX9D6RGY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC45A2	ENST00000296589.9 linkuse as main transcript	c.1121delT	p.Leu374fs	frameshift_variant	5/7	1	NM_016180.5	ENSP00000296589.4	Q9UMX9-1
SLC45A2	ENST00000382102.7 linkuse as main transcript	c.1121delT	p.Leu374fs	frameshift_variant	5/6	1		ENSP00000371534.3	Q9UMX9-4
SLC45A2	ENST00000509381 linkuse as main transcript	c.*63delT		3_prime_UTR_variant	4/4	1		ENSP00000421100.1	D6RGY6
SLC45A2	ENST00000510600.1 linkuse as main transcript	c.596delT	p.Leu199fs	frameshift_variant	4/5	3		ENSP00000424010.1	D6RBP8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Oculocutaneous albinism type 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4506). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 16868655). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe374Serfs*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). -

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