7-23256914-G-A

Variant names:

• chr7-23256914-G-A
• rs199355
• NM_002510.3:c.390G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_002510.3(GPNMB):​c.390G>A​(p.Pro130Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,612,572 control chromosomes in the GnomAD database, including 128,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.41 (13432 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115373 hom.)
• Consequence: GPNMB NM_002510.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.551
• Publications: 41 publications found

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]

GPNMB Gene-Disease associations (from GenCC):

• amyloidosis, primary localized cutaneous, 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-23256914-G-A is Benign according to our data. Variant chr7-23256914-G-A is described in ClinVar as [Benign]. Clinvar id is 3059129.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.551 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPNMB	NM_002510.3	c.390G>A	p.Pro130Pro	synonymous_variant	Exon 4 of 11	ENST00000258733.9	NP_002501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPNMB	ENST00000258733.9	c.390G>A	p.Pro130Pro	synonymous_variant	Exon 4 of 11	1	NM_002510.3	ENSP00000258733.5

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62963 AN: 152028 Hom.: 13423 Cov.: 33

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.363 AC: 91234 AN: 251092 AF XY: 0.369

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.135

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.390

GnomAD4 exome AF: 0.393 AC: 574575 AN: 1460426 Hom.: 115373 Cov.: 36 AF XY: 0.393 AC XY: 285465 AN XY: 726578

African (AFR) AF: 0.503 AC: 16815 AN: 33450

American (AMR) AF: 0.271 AC: 12108 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 11101 AN: 26124

East Asian (EAS) AF: 0.191 AC: 7565 AN: 39694

South Asian (SAS) AF: 0.365 AC: 31478 AN: 86210

European-Finnish (FIN) AF: 0.373 AC: 19946 AN: 53406

Middle Eastern (MID) AF: 0.430 AC: 2478 AN: 5768

European-Non Finnish (NFE) AF: 0.404 AC: 449058 AN: 1110724

Other (OTH) AF: 0.398 AC: 24026 AN: 60362

GnomAD4 genome AF: 0.414 AC: 63010 AN: 152146 Hom.: 13432 Cov.: 33 AF XY: 0.410 AC XY: 30481 AN XY: 74386

African (AFR) AF: 0.490 AC: 20343 AN: 41482

American (AMR) AF: 0.371 AC: 5675 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1520 AN: 3472

East Asian (EAS) AF: 0.141 AC: 731 AN: 5174

South Asian (SAS) AF: 0.363 AC: 1749 AN: 4824

European-Finnish (FIN) AF: 0.366 AC: 3875 AN: 10576

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27791 AN: 67998

Other (OTH) AF: 0.435 AC: 918 AN: 2110

Alfa AF: 0.410 Hom.: 24398

Bravo AF: 0.415

Asia WGS AF: 0.330 AC: 1148 AN: 3478

EpiCase AF: 0.415

EpiControl AF: 0.409

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GPNMB-related disorder Benign:1

Oct 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.16
DANN	Benign	0.70
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199355; hg19: chr7-23296533; COSMIC: COSV51696947; COSMIC: COSV51696947;