chr7-23260036-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_002510.3(GPNMB):c.598A>G(p.Asn200Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
GPNMB
NM_002510.3 missense
NM_002510.3 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 8.13
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity GPNMB_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPNMB | NM_002510.3 | c.598A>G | p.Asn200Asp | missense_variant | 5/11 | ENST00000258733.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPNMB | ENST00000258733.9 | c.598A>G | p.Asn200Asp | missense_variant | 5/11 | 1 | NM_002510.3 | ||
GPNMB | ENST00000381990.6 | c.598A>G | p.Asn200Asp | missense_variant | 5/11 | 1 | |||
GPNMB | ENST00000647578.1 | c.598A>G | p.Asn200Asp | missense_variant | 5/12 | P1 | |||
GPNMB | ENST00000465673.5 | n.776A>G | non_coding_transcript_exon_variant | 6/6 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251452Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135904
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461766Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727198
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2022 | The c.598A>G (p.N200D) alteration is located in exon 5 (coding exon 5) of the GPNMB gene. This alteration results from a A to G substitution at nucleotide position 598, causing the asparagine (N) at amino acid position 200 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.
REVEL
Benign
Sift
Uncertain
D;T;.
Sift4G
Uncertain
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0582);Loss of MoRF binding (P = 0.0582);Loss of MoRF binding (P = 0.0582);
MVP
MPC
0.41
ClinPred
D
GERP RS
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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