7-23256953-C-T

Variant names:

• chr7-23256953-C-T
• rs199354
• NM_002510.3:c.429C>T

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.429C>T​(p.Asp143Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,613,802 control chromosomes in the GnomAD database, including 1,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.043 (209 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1334 hom.)
• Consequence: GPNMB NM_002510.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.771
• Publications: 10 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=-0.55).
• BP6: Variant 7-23256953-C-T is Benign according to our data. Variant chr7-23256953-C-T is described in ClinVar as [Benign]. Clinvar id is 3055318.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.771 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPNMB	NM_002510.3	c.429C>T	p.Asp143Asp	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.429C>T	p.Asp143Asp	synonymous_variant	Exon 4 of 11	1	NM_002510.3	ENSP00000258733.5

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6508 AN: 152120 Hom.: 209 Cov.: 33

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0445

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0986

Gnomad FIN AF: 0.0984

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0465 AC: 11681 AN: 251456 AF XY: 0.0493

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0970

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0490

GnomAD4 exome AF: 0.0329 AC: 48020 AN: 1461564 Hom.: 1334 Cov.: 32 AF XY: 0.0348 AC XY: 25326 AN XY: 727102

African (AFR) AF: 0.0553 AC: 1851 AN: 33468

American (AMR) AF: 0.0448 AC: 2004 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 1287 AN: 26132

East Asian (EAS) AF: 0.0193 AC: 766 AN: 39700

South Asian (SAS) AF: 0.0995 AC: 8582 AN: 86238

European-Finnish (FIN) AF: 0.100 AC: 5343 AN: 53420

Middle Eastern (MID) AF: 0.0602 AC: 347 AN: 5768

European-Non Finnish (NFE) AF: 0.0231 AC: 25664 AN: 1111730

Other (OTH) AF: 0.0360 AC: 2176 AN: 60384

GnomAD4 genome AF: 0.0428 AC: 6523 AN: 152238 Hom.: 209 Cov.: 33 AF XY: 0.0473 AC XY: 3519 AN XY: 74420

African (AFR) AF: 0.0541 AC: 2247 AN: 41556

American (AMR) AF: 0.0447 AC: 684 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.00850 AC: 44 AN: 5174

South Asian (SAS) AF: 0.0985 AC: 475 AN: 4822

European-Finnish (FIN) AF: 0.0984 AC: 1042 AN: 10588

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0257 AC: 1750 AN: 68020

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0298 Hom.: 229

Bravo AF: 0.0380

Asia WGS AF: 0.0580 AC: 203 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0261

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GPNMB-related disorder Benign:1

Feb 28, 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	-0.55
CADD	Benign	6.6
DANN	Benign	0.66
PhyloP100		0.77
Mutation Taster		=100/0	polymorphism (auto)

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: rs199354; hg19: chr7-23296572;