rs773435101

Positions:

• chr7-23260626-CTGTT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002510.3(GPNMB):​c.877_880del​(p.Val293ProfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPNMB NM_002510.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.60

Genes affected

GPNMB (HGNC:4462): (glycoprotein nmb) The protein encoded by this gene is a type I transmembrane glycoprotein which shows homology to the pMEL17 precursor, a melanocyte-specific protein. GPNMB shows expression in the lowly metastatic human melanoma cell lines and xenografts but does not show expression in the highly metastatic cell lines. GPNMB may be involved in growth delay and reduction of metastatic potential. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 7-23260626-CTGTT-C is Pathogenic according to our data. Variant chr7-23260626-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 503502.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPNMB	NM_002510.3	c.877_880del	p.Val293ProfsTer6	frameshift_variant	6/11	ENST00000258733.9	NP_002501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPNMB	ENST00000258733.9	c.877_880del	p.Val293ProfsTer6	frameshift_variant	6/11	1	NM_002510.3	ENSP00000258733
GPNMB	ENST00000381990.6	c.877_880del	p.Val293ProfsTer6	frameshift_variant	6/11	1		ENSP00000371420
GPNMB	ENST00000647578.1	c.877_880del	p.Val293ProfsTer6	frameshift_variant	6/12			ENSP00000497362	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amyloidosis, primary localized cutaneous, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 27, 2018

- -

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: rs773435101; hg19: chr7-23300245;