rs387906317

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 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 has been classified as Pathogenic. 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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 4500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016180.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC45A2	NM_016180.5	MANE Select	c.986delC	p.Thr329LysfsTer69	frameshift	Exon 4 of 7	NP_057264.4
	SLC45A2	NM_001012509.4		c.986delC	p.Thr329LysfsTer69	frameshift	Exon 4 of 6	NP_001012527.2	Q9UMX9-4
	SLC45A2	NM_001297417.4		c.660delC	p.Asp220GlufsTer79	frameshift	Exon 3 of 4	NP_001284346.2	D6RGY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC45A2	ENST00000296589.9	TSL:1 MANE Select	c.986delC	p.Thr329LysfsTer69	frameshift	Exon 4 of 7	ENSP00000296589.4	Q9UMX9-1
	SLC45A2	ENST00000382102.7	TSL:1	c.986delC	p.Thr329LysfsTer69	frameshift	Exon 4 of 6	ENSP00000371534.3	Q9UMX9-4
	SLC45A2	ENST00000509381.1	TSL:1	c.660delC	p.Asp220GlufsTer79	frameshift	Exon 3 of 4	ENSP00000421100.1	D6RGY6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Oculocutaneous albinism type 4 (1)
1	-	-	SKIN/HAIR/EYE PIGMENTATION 5, BLACK/NONBLACK HAIR (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906317; hg19: chr5-33954511;