7-23260029-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002510.3(GPNMB):c.591C>G(p.Asn197Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,614,046 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. N197H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (15 hom.)
• Consequence: GPNMB NM_002510.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020676255).
• BP6: Variant 7-23260029-C-G is Benign according to our data. Variant chr7-23260029-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 718718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00221 (336/152272) while in subpopulation NFE AF= 0.00365 (248/68024). AF 95% confidence interval is 0.00327. There are 1 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPNMB	NM_002510.3	c.591C>G	p.Asn197Lys	missense_variant	5/11	ENST00000258733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPNMB	ENST00000258733.9	c.591C>G	p.Asn197Lys	missense_variant	5/11	1	NM_002510.3
GPNMB	ENST00000381990.6	c.591C>G	p.Asn197Lys	missense_variant	5/11	1
GPNMB	ENST00000647578.1	c.591C>G	p.Asn197Lys	missense_variant	5/12			P1
GPNMB	ENST00000465673.5	n.769C>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00193 AC: 485 AN: 251456 Hom.: 2 AF XY: 0.00183 AC XY: 249 AN XY: 135906

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00400 AC: 5841 AN: 1461774 Hom.: 15 Cov.: 31 AF XY: 0.00384 AC XY: 2796 AN XY: 727198

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00494

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74462

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000184 Hom.: 12

Bravo AF: 0.00226

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00545 AC: 21

ExAC AF: 0.00170 AC: 206

EpiCase AF: 0.00311

EpiControl AF: 0.00308

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GPNMB: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.75
MutPred		0.51		Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);
MVP		0.56
MPC		0.37
ClinPred		0.030	T
GERP RS		5.0
Varity_R		0.48
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17147995; hg19: chr7-23299648; COSMIC: COSV51696977; COSMIC: COSV51696977;