Menu
GeneBe

7-23260003-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_002510.3(GPNMB):c.565C>T(p.Arg189Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

GPNMB
NM_002510.3 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.90
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-23260003-C-T is Pathogenic according to our data. Variant chr7-23260003-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 503497.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPNMBNM_002510.3 linkuse as main transcriptc.565C>T p.Arg189Ter stop_gained 5/11 ENST00000258733.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPNMBENST00000258733.9 linkuse as main transcriptc.565C>T p.Arg189Ter stop_gained 5/111 NM_002510.3 Q14956-2
GPNMBENST00000381990.6 linkuse as main transcriptc.565C>T p.Arg189Ter stop_gained 5/111 Q14956-1
GPNMBENST00000647578.1 linkuse as main transcriptc.565C>T p.Arg189Ter stop_gained 5/12 P1
GPNMBENST00000465673.5 linkuse as main transcriptn.743C>T non_coding_transcript_exon_variant 6/65

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000164
AC:
25
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00211
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000199
AC:
50
AN:
251398
Hom.:
0
AF XY:
0.000213
AC XY:
29
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00223
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000163
AC:
238
AN:
1461794
Hom.:
0
Cov.:
31
AF XY:
0.000168
AC XY:
122
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00103
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000167
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000164
AC:
25
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00212
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000956
Hom.:
0
Bravo
AF:
0.000147
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000123
AC:
15
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyloidosis, primary localized cutaneous, 3 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 08, 2019- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 27, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
37
Dann
Uncertain
1.0
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.85
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.82
GERP RS
4.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs140352180; hg19: chr7-23299622; COSMIC: COSV51701184; COSMIC: COSV51701184; API