NM_002510.3:c.267C>T

Variant names:

• chr7-23254212-C-T
• rs113932410
• NM_002510.3:c.267C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_002510.3(GPNMB):​c.267C>T​(p.Leu89Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,614,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: GPNMB NM_002510.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.264
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 7-23254212-C-T is Benign according to our data. Variant chr7-23254212-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 751924.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.264 with no splicing effect.

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.267C>T	p.Leu89Leu	synonymous	Exon 3 of 11	NP_002501.1	Q14956-2
	GPNMB	NM_001005340.2		c.267C>T	p.Leu89Leu	synonymous	Exon 3 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.267C>T	p.Leu89Leu	synonymous	Exon 3 of 11	ENSP00000258733.5	Q14956-2
	GPNMB	ENST00000381990.6	TSL:1	c.267C>T	p.Leu89Leu	synonymous	Exon 3 of 11	ENSP00000371420.2	Q14956-1
	GPNMB	ENST00000409458.3	TSL:1	c.267C>T	p.Leu89Leu	synonymous	Exon 3 of 4	ENSP00000386476.3	Q96F58

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000636 AC: 16 AN: 251424 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461784 Hom.: 1 Cov.: 31 AF XY: 0.000151 AC XY: 110 AN XY: 727206

African (AFR) AF: 0.000926 AC: 31 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000129 AC: 143 AN: 1111924

Other (OTH) AF: 0.000762 AC: 46 AN: 60394

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74474

African (AFR) AF: 0.000553 AC: 23 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.000185

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113932410; hg19: chr7-23293831;