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GeneBe

7-23256953-C-T

Variant summary

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

The NM_002510.3(GPNMB):c.429C>T(p.Asp143=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,613,802 control chromosomes in the GnomAD database, including 1,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.043 ( 209 hom., cov: 33)
Exomes 𝑓: 0.033 ( 1334 hom. )

Consequence

GPNMB
NM_002510.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.771
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=-0.55).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-23256953-C-T is Benign according to our data. Variant chr7-23256953-C-T is described in ClinVar as [Benign]. Clinvar id is 3055318.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=0.771 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0912 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPNMBNM_002510.3 linkuse as main transcriptc.429C>T p.Asp143= synonymous_variant 4/11 ENST00000258733.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPNMBENST00000258733.9 linkuse as main transcriptc.429C>T p.Asp143= synonymous_variant 4/111 NM_002510.3 Q14956-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0428
AC:
6508
AN:
152120
Hom.:
209
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0539
Gnomad AMI
AF:
0.00658
Gnomad AMR
AF:
0.0445
Gnomad ASJ
AF:
0.0522
Gnomad EAS
AF:
0.00868
Gnomad SAS
AF:
0.0986
Gnomad FIN
AF:
0.0984
Gnomad MID
AF:
0.0348
Gnomad NFE
AF:
0.0257
Gnomad OTH
AF:
0.0402
GnomAD3 exomes
AF:
0.0465
AC:
11681
AN:
251456
Hom.:
397
AF XY:
0.0493
AC XY:
6695
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0561
Gnomad AMR exome
AF:
0.0430
Gnomad ASJ exome
AF:
0.0492
Gnomad EAS exome
AF:
0.0113
Gnomad SAS exome
AF:
0.101
Gnomad FIN exome
AF:
0.0970
Gnomad NFE exome
AF:
0.0271
Gnomad OTH exome
AF:
0.0490
GnomAD4 exome
AF:
0.0329
AC:
48020
AN:
1461564
Hom.:
1334
Cov.:
32
AF XY:
0.0348
AC XY:
25326
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.0553
Gnomad4 AMR exome
AF:
0.0448
Gnomad4 ASJ exome
AF:
0.0493
Gnomad4 EAS exome
AF:
0.0193
Gnomad4 SAS exome
AF:
0.0995
Gnomad4 FIN exome
AF:
0.100
Gnomad4 NFE exome
AF:
0.0231
Gnomad4 OTH exome
AF:
0.0360
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0428
AC:
6523
AN:
152238
Hom.:
209
Cov.:
33
AF XY:
0.0473
AC XY:
3519
AN XY:
74420
show subpopulations
Gnomad4 AFR
AF:
0.0541
Gnomad4 AMR
AF:
0.0447
Gnomad4 ASJ
AF:
0.0522
Gnomad4 EAS
AF:
0.00850
Gnomad4 SAS
AF:
0.0985
Gnomad4 FIN
AF:
0.0984
Gnomad4 NFE
AF:
0.0257
Gnomad4 OTH
AF:
0.0397
Alfa
AF:
0.0291
Hom.:
109
Bravo
AF:
0.0380
Asia WGS
AF:
0.0580
AC:
203
AN:
3478
EpiCase
AF:
0.0246
EpiControl
AF:
0.0261

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 SciencesFeb 28, 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
-0.55
Cadd
Benign
6.6
Dann
Benign
0.66

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs199354; hg19: chr7-23296572; API