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GeneBe

7-23256914-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_002510.3(GPNMB):c.390G>A(p.Pro130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,612,572 control chromosomes in the GnomAD database, including 128,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.41 ( 13432 hom., cov: 33)
Exomes 𝑓: 0.39 ( 115373 hom. )

Consequence

GPNMB
NM_002510.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.551
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-23256914-G-A is Benign according to our data. Variant chr7-23256914-G-A is described in ClinVar as [Benign]. Clinvar id is 3059129.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.551 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPNMBNM_002510.3 linkuse as main transcriptc.390G>A p.Pro130= synonymous_variant 4/11 ENST00000258733.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPNMBENST00000258733.9 linkuse as main transcriptc.390G>A p.Pro130= synonymous_variant 4/111 NM_002510.3 Q14956-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.414
AC:
62963
AN:
152028
Hom.:
13423
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.491
Gnomad AMI
AF:
0.304
Gnomad AMR
AF:
0.371
Gnomad ASJ
AF:
0.438
Gnomad EAS
AF:
0.142
Gnomad SAS
AF:
0.363
Gnomad FIN
AF:
0.366
Gnomad MID
AF:
0.440
Gnomad NFE
AF:
0.409
Gnomad OTH
AF:
0.431
GnomAD3 exomes
AF:
0.363
AC:
91234
AN:
251092
Hom.:
17657
AF XY:
0.369
AC XY:
50028
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.494
Gnomad AMR exome
AF:
0.257
Gnomad ASJ exome
AF:
0.423
Gnomad EAS exome
AF:
0.135
Gnomad SAS exome
AF:
0.369
Gnomad FIN exome
AF:
0.364
Gnomad NFE exome
AF:
0.405
Gnomad OTH exome
AF:
0.390
GnomAD4 exome
AF:
0.393
AC:
574575
AN:
1460426
Hom.:
115373
Cov.:
36
AF XY:
0.393
AC XY:
285465
AN XY:
726578
show subpopulations
Gnomad4 AFR exome
AF:
0.503
Gnomad4 AMR exome
AF:
0.271
Gnomad4 ASJ exome
AF:
0.425
Gnomad4 EAS exome
AF:
0.191
Gnomad4 SAS exome
AF:
0.365
Gnomad4 FIN exome
AF:
0.373
Gnomad4 NFE exome
AF:
0.404
Gnomad4 OTH exome
AF:
0.398
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.414
AC:
63010
AN:
152146
Hom.:
13432
Cov.:
33
AF XY:
0.410
AC XY:
30481
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.490
Gnomad4 AMR
AF:
0.371
Gnomad4 ASJ
AF:
0.438
Gnomad4 EAS
AF:
0.141
Gnomad4 SAS
AF:
0.363
Gnomad4 FIN
AF:
0.366
Gnomad4 NFE
AF:
0.409
Gnomad4 OTH
AF:
0.435
Alfa
AF:
0.410
Hom.:
18930
Bravo
AF:
0.415
Asia WGS
AF:
0.330
AC:
1148
AN:
3478
EpiCase
AF:
0.415
EpiControl
AF:
0.409

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

GPNMB-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 23, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
Cadd
Benign
0.16
Dann
Benign
0.70

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199355; hg19: chr7-23296533; COSMIC: COSV51696947; COSMIC: COSV51696947; API