NM_002510.3:c.49T>C

Variant names:

• chr7-23246906-T-C
• rs35519567
• NM_002510.3:c.49T>C

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.49T>C​(p.Leu17Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,584 control chromosomes in the GnomAD database, including 654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.034 (244 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (410 hom.)
• Consequence: GPNMB NM_002510.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.89
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-23246906-T-C is Benign according to our data. Variant chr7-23246906-T-C is described in ClinVar as Benign. ClinVar VariationId is 3042316.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002510.3. 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
	GPNMB	NM_002510.3	MANE Select	c.49T>C	p.Leu17Leu	synonymous	Exon 1 of 11	NP_002501.1	Q14956-2
	GPNMB	NM_001005340.2		c.49T>C	p.Leu17Leu	synonymous	Exon 1 of 11	NP_001005340.1	Q14956-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPNMB	ENST00000258733.9	TSL:1 MANE Select	c.49T>C	p.Leu17Leu	synonymous	Exon 1 of 11	ENSP00000258733.5	Q14956-2
	GPNMB	ENST00000381990.6	TSL:1	c.49T>C	p.Leu17Leu	synonymous	Exon 1 of 11	ENSP00000371420.2	Q14956-1
	GPNMB	ENST00000409458.3	TSL:1	c.49T>C	p.Leu17Leu	synonymous	Exon 1 of 4	ENSP00000386476.3	Q96F58

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5102 AN: 152132 Hom.: 244 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.00893

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0191 AC: 4802 AN: 251492 AF XY: 0.0164

Gnomad AFR exome AF: 0.0968

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00884 AC: 12913 AN: 1461334 Hom.: 410 Cov.: 29 AF XY: 0.00835 AC XY: 6068 AN XY: 727042

African (AFR) AF: 0.0968 AC: 3237 AN: 33424

American (AMR) AF: 0.00724 AC: 324 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26132

East Asian (EAS) AF: 0.0983 AC: 3900 AN: 39692

South Asian (SAS) AF: 0.00555 AC: 479 AN: 86246

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53420

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5766

European-Non Finnish (NFE) AF: 0.00353 AC: 3924 AN: 1111556

Other (OTH) AF: 0.0159 AC: 958 AN: 60376

GnomAD4 genome AF: 0.0336 AC: 5114 AN: 152250 Hom.: 244 Cov.: 32 AF XY: 0.0335 AC XY: 2493 AN XY: 74456

African (AFR) AF: 0.0948 AC: 3936 AN: 41524

American (AMR) AF: 0.0143 AC: 219 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.124 AC: 641 AN: 5184

South Asian (SAS) AF: 0.00894 AC: 43 AN: 4812

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68016

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.0141 Hom.: 63

Bravo AF: 0.0376

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00456

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GPNMB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.42
PhyloP100		-1.9
PromoterAI		-0.023	Neutral
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: rs35519567; hg19: chr7-23286525; COSMIC: COSV51697234; COSMIC: COSV51697234;