chr7-23256954-G-T

Variant names:

• chr7-23256954-G-T
• rs201016099
• NM_002510.3:c.430G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002510.3(GPNMB):​c.430G>T​(p.Gly144Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G144R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GPNMB NM_002510.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.766
• Publications: 3 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04286921).
• BP6: Variant 7-23256954-G-T is Benign according to our data. Variant chr7-23256954-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 4031332.Status of the report is criteria_provided_single_submitter, 1 stars.

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.430G>T	p.Gly144Trp	missense	Exon 4 of 11	NP_002501.1	Q14956-2
	GPNMB	NM_001005340.2		c.430G>T	p.Gly144Trp	missense	Exon 4 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.430G>T	p.Gly144Trp	missense	Exon 4 of 11	ENSP00000258733.5	Q14956-2
	GPNMB	ENST00000381990.6	TSL:1	c.430G>T	p.Gly144Trp	missense	Exon 4 of 11	ENSP00000371420.2	Q14956-1
	GPNMB	ENST00000409458.3	TSL:1	c.430G>T	p.Gly144Trp	missense	Exon 4 of 4	ENSP00000386476.3	Q96F58

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.31
DANN	Benign	0.58
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.5	N
PhyloP100		0.77
PrimateAI	Benign	0.27	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.066
Sift	Benign	0.39	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.20		Loss of sheet (P = 0.0228)
MVP		0.19
MPC		0.083
ClinPred		0.42	T
GERP RS		-2.2
Varity_R		0.029
gMVP		0.54
Mutation Taster		=91/9	polymorphism

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: rs201016099; hg19: chr7-23296573;