rs387906317

Variant names:

• chr5-33954406-TG-T
• rs387906317
• NM_016180.5:c.986delC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016180.5(SLC45A2):​c.986delC​(p.Thr329LysfsTer69) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T329T) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC45A2 NM_016180.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 5-33954406-TG-T is Pathogenic according to our data. Variant chr5-33954406-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 4500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-33954406-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC45A2	NM_016180.5	c.986delC	p.Thr329LysfsTer69	frameshift_variant	Exon 4 of 7	ENST00000296589.9	NP_057264.4
SLC45A2	NM_001012509.4	c.986delC	p.Thr329LysfsTer69	frameshift_variant	Exon 4 of 6		NP_001012527.2
SLC45A2	NM_001297417.4	c.660delC	p.Asp220GlufsTer79	frameshift_variant	Exon 3 of 4		NP_001284346.2
SLC45A2	XM_047417259.1	c.746delC	p.Thr249LysfsTer69	frameshift_variant	Exon 4 of 7		XP_047273215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC45A2	ENST00000296589.9	c.986delC	p.Thr329LysfsTer69	frameshift_variant	Exon 4 of 7	1	NM_016180.5	ENSP00000296589.4
SLC45A2	ENST00000382102.7	c.986delC	p.Thr329LysfsTer69	frameshift_variant	Exon 4 of 6	1		ENSP00000371534.3
SLC45A2	ENST00000509381.1	c.660delC	p.Asp220GlufsTer79	frameshift_variant	Exon 3 of 4	1		ENSP00000421100.1
SLC45A2	ENST00000510600.1	c.461delC	p.Thr154LysfsTer69	frameshift_variant	Exon 3 of 5	3		ENSP00000424010.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 20, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the homozygous state or in the presence of another SLC45A2 variant in individuals with oculocutaneous albinism in the literature (PMID: 28170084, 14722913); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21677667, 14722913, 28976636, Moreno-Artero2022[paper], 28298193, 24096233, 36553465, 28170084) -

SKIN/HAIR/EYE PIGMENTATION 5, BLACK/NONBLACK HAIR Pathogenic:1

Mar 10, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism type 4 Pathogenic:1

Feb 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs387906317; hg19: chr5-33954511;