chr7-23266401-T-C

Variant names:

• chr7-23266401-T-C
• rs156429
• NM_002510.3:c.1019-116T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002510.3(GPNMB):​c.1019-116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 917,452 control chromosomes in the GnomAD database, including 90,665 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (24559 hom., cov: 32)
  • Exomes 𝑓: 0.40 (66106 hom.)
• Consequence: GPNMB NM_002510.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 35 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPNMB	NM_002510.3	c.1019-116T>C		intron_variant	Intron 6 of 10	ENST00000258733.9	NP_002501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPNMB	ENST00000258733.9	c.1019-116T>C		intron_variant	Intron 6 of 10	1	NM_002510.3	ENSP00000258733.5
GPNMB	ENST00000381990.6	c.1019-80T>C		intron_variant	Intron 6 of 10	1		ENSP00000371420.2
GPNMB	ENST00000479625.1	n.262T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2
GPNMB	ENST00000647578.1	c.1103-116T>C		intron_variant	Intron 7 of 11			ENSP00000497362.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79830 AN: 151984 Hom.: 24498 Cov.: 32

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.404 AC: 309300 AN: 765350 Hom.: 66106 Cov.: 10 AF XY: 0.402 AC XY: 159737 AN XY: 397718

African (AFR) AF: 0.882 AC: 16975 AN: 19248

American (AMR) AF: 0.305 AC: 8861 AN: 29018

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 7367 AN: 17166

East Asian (EAS) AF: 0.279 AC: 9993 AN: 35782

South Asian (SAS) AF: 0.379 AC: 22065 AN: 58288

European-Finnish (FIN) AF: 0.374 AC: 17482 AN: 46754

Middle Eastern (MID) AF: 0.484 AC: 1836 AN: 3790

European-Non Finnish (NFE) AF: 0.403 AC: 208940 AN: 518780

Other (OTH) AF: 0.432 AC: 15781 AN: 36524

GnomAD4 genome AF: 0.526 AC: 79947 AN: 152102 Hom.: 24559 Cov.: 32 AF XY: 0.519 AC XY: 38571 AN XY: 74340

African (AFR) AF: 0.869 AC: 36057 AN: 41500

American (AMR) AF: 0.409 AC: 6240 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1350 AN: 5166

South Asian (SAS) AF: 0.382 AC: 1844 AN: 4822

European-Finnish (FIN) AF: 0.364 AC: 3850 AN: 10574

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27536 AN: 67986

Other (OTH) AF: 0.509 AC: 1071 AN: 2106

Alfa AF: 0.457 Hom.: 29094

Bravo AF: 0.541

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.77
DANN	Benign	0.46
PhyloP100		-0.054
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: rs156429; hg19: chr7-23306020; COSMIC: COSV51697980; COSMIC: COSV51697980;