X-133692376-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004484.4(GPC3):c.1285G>A(p.Val429Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,210,255 control chromosomes in the GnomAD database, including 24 homozygotes. There are 1,849 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0035 ( 3 hom., 115 hem., cov: 24)
Exomes 𝑓: 0.0047 ( 21 hom. 1734 hem. )
Consequence
GPC3
NM_004484.4 missense
NM_004484.4 missense
Scores
7
9
Clinical Significance
Conservation
PhyloP100: 2.92
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.008226454).
BP6
Variant X-133692376-C-T is Benign according to our data. Variant chrX-133692376-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133692376-C-T is described in Lovd as [Likely_benign]. Variant chrX-133692376-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00351 (397/113221) while in subpopulation AMR AF= 0.0104 (112/10747). AF 95% confidence interval is 0.00886. There are 3 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 XL gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00350 AC: 396AN: 113168Hom.: 3 Cov.: 24 AF XY: 0.00326 AC XY: 115AN XY: 35304
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GnomAD3 exomes AF: 0.00625 AC: 1146AN: 183404Hom.: 11 AF XY: 0.00587 AC XY: 398AN XY: 67854
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GnomAD4 exome AF: 0.00469 AC: 5144AN: 1097034Hom.: 21 Cov.: 29 AF XY: 0.00478 AC XY: 1734AN XY: 362442
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GnomAD4 genome AF: 0.00351 AC: 397AN: 113221Hom.: 3 Cov.: 24 AF XY: 0.00325 AC XY: 115AN XY: 35367
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:6
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 05, 2016 | Variant summary: The GPC3 variant, c.1285G>A (p.Val429Met) causes a missense change involving a conserved nucleotide with 2/3 in silico programs (SNPs&GO and MutationTaster not captured here due to low reliability index and p-value, respectively) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 511/87700 (1/171, 188 hemizygotes, 5 homozygotes), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic GPC3 variant of 1/10000000. The variant of interest, to our knowledge, has not been reported in affected individuals via publications. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 14, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 09, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Benign:2Other:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Simpson-Golabi-Behmel syndrome type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Wilms tumor 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2025 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
B;.;.
Vest4
MVP
MPC
0.70
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