chr7-23256945-G-T
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1
The NM_002510.3(GPNMB):c.421G>T(p.Asp141Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0016 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
GPNMB
NM_002510.3 missense
NM_002510.3 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 2.44
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 -14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0037172139).
BP6
?
Variant 7-23256945-G-T is Benign according to our data. Variant chr7-23256945-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 733291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00156 (237/152344) while in subpopulation AFR AF= 0.00541 (225/41580). AF 95% confidence interval is 0.00483. There are 1 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPNMB | NM_002510.3 | c.421G>T | p.Asp141Tyr | missense_variant | 4/11 | ENST00000258733.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPNMB | ENST00000258733.9 | c.421G>T | p.Asp141Tyr | missense_variant | 4/11 | 1 | NM_002510.3 |
Frequencies
GnomAD3 genomes ? AF: 0.00155 AC: 236AN: 152226Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000370 AC: 93AN: 251450Hom.: 1 AF XY: 0.000243 AC XY: 33AN XY: 135902
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GnomAD4 exome AF: 0.000148 AC: 217AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.000125 AC XY: 91AN XY: 727230
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GnomAD4 genome ? AF: 0.00156 AC: 237AN: 152344Hom.: 1 Cov.: 33 AF XY: 0.00153 AC XY: 114AN XY: 74496
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
GPNMB-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 16, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;.
REVEL
Benign
Sift
Uncertain
D;D;D;.
Sift4G
Uncertain
D;D;D;.
Polyphen
D;D;D;.
Vest4
MVP
MPC
0.30
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at