chrX-133753638-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004484.4(GPC3):​c.876T>G​(p.Ile292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,666 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I292T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

GPC3
NM_004484.4 missense

Scores

7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.364

Publications

0 publications found
Variant links:
Genes affected
GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
GPC3 Gene-Disease associations (from GenCC):
  • Simpson-Golabi-Behmel syndrome
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • Simpson-Golabi-Behmel syndrome type 1
    Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPC3NM_004484.4 linkc.876T>G p.Ile292Met missense_variant Exon 3 of 8 ENST00000370818.8 NP_004475.1 P51654-1Q53H15I6QTG3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPC3ENST00000370818.8 linkc.876T>G p.Ile292Met missense_variant Exon 3 of 8 1 NM_004484.4 ENSP00000359854.3 P51654-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD2 exomes
AF:
0.0000327
AC:
6
AN:
183334
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000433
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097666
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
363036
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26393
American (AMR)
AF:
0.00
AC:
0
AN:
35206
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19384
East Asian (EAS)
AF:
0.0000662
AC:
2
AN:
30202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54132
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40530
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4136
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
841610
Other (OTH)
AF:
0.00
AC:
0
AN:
46073
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
23
Alfa
AF:
0.00
Hom.:
2
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

Wilms tumor 1 Uncertain:1
Nov 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 292 of the GPC3 protein (p.Ile292Met). This variant is present in population databases (rs61754633, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 843877). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GPC3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T;.;.
FATHMM_MKL
Benign
0.31
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.46
T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
2.0
M;M;.
PhyloP100
-0.36
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-1.5
N;N;.
REVEL
Uncertain
0.30
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.69
MutPred
0.52
Loss of ubiquitination at K294 (P = 0.0727);Loss of ubiquitination at K294 (P = 0.0727);.;
MVP
0.73
MPC
0.65
ClinPred
0.35
T
GERP RS
1.7
PromoterAI
0.011
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.59
gMVP
0.63
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs61754633; hg19: chrX-132887665; API