7-23260029-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002510.3(GPNMB):c.591C>T(p.Asn197=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,042 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (150 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (141 hom.)
• Consequence: GPNMB NM_002510.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.58

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 7-23260029-C-T is Benign according to our data. Variant chr7-23260029-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 778296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPNMB	NM_002510.3	c.591C>T	p.Asn197=	synonymous_variant	5/11	ENST00000258733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPNMB	ENST00000258733.9	c.591C>T	p.Asn197=	synonymous_variant	5/11	1	NM_002510.3
GPNMB	ENST00000381990.6	c.591C>T	p.Asn197=	synonymous_variant	5/11	1
GPNMB	ENST00000647578.1	c.591C>T	p.Asn197=	synonymous_variant	5/12			P1
GPNMB	ENST00000465673.5	n.769C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3805 AN: 152148 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00812 AC: 2042 AN: 251456 Hom.: 66 AF XY: 0.00658 AC XY: 894 AN XY: 135906

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00520 AC: 7606 AN: 1461776 Hom.: 141 Cov.: 31 AF XY: 0.00486 AC XY: 3531 AN XY: 727196

Gnomad4 AFR exome AF: 0.0830

Gnomad4 AMR exome AF: 0.00646

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00775

GnomAD4 genome AF: 0.0251 AC: 3815 AN: 152266 Hom.: 150 Cov.: 32 AF XY: 0.0243 AC XY: 1807 AN XY: 74456

Gnomad4 AFR AF: 0.0806

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00626 Hom.: 12

Bravo AF: 0.0283

EpiCase AF: 0.00398

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

GPNMB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

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	-0.35
Cadd	Benign	7.8
Dann	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs17147995; hg19: chr7-23299648; COSMIC: COSV51700060; COSMIC: COSV51700060;