rs182950534

chrX-133692502-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004484.4(GPC3):c.1167-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,201,309 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,621 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., 96 hem., cov: 24)
  • Exomes 𝑓: 0.0045 (9 hom. 1525 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001398
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.690

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-133692502-A-G is Benign according to our data. Variant chrX-133692502-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 239934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133692502-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.1167-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.1167-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004484.4	P1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 331 AN: 112673 Hom.: 2 Cov.: 24 AF XY: 0.00276 AC XY: 96 AN XY: 34799

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00129

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.00854

GnomAD3 exomes AF: 0.00251 AC: 458 AN: 182449 Hom.: 0 AF XY: 0.00243 AC XY: 163 AN XY: 67141

Gnomad AFR exome AF: 0.000686

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00100

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00451 AC: 4907 AN: 1088583 Hom.: 9 Cov.: 27 AF XY: 0.00430 AC XY: 1525 AN XY: 354389

Gnomad4 AFR exome AF: 0.000839

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.000104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000742

Gnomad4 FIN exome AF: 0.00111

Gnomad4 NFE exome AF: 0.00545

Gnomad4 OTH exome AF: 0.00395

GnomAD4 genome AF: 0.00293 AC: 330 AN: 112726 Hom.: 2 Cov.: 24 AF XY: 0.00275 AC XY: 96 AN XY: 34862

Gnomad4 AFR AF: 0.000869

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00129

Gnomad4 NFE AF: 0.00441

Gnomad4 OTH AF: 0.00843

Alfa AF: 0.00346 Hom.: 25

Bravo AF: 0.00327

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 14, 2018	Variant summary: GPC3 c.1167-8T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0025 in 199497 control chromosomes in the gnomAD database, including 1 homozygote and 179 hemizygotes. The observed variant frequency is approximately 39459-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in GPC3 causing Wilms Tumor, Type 1 phenotype (6.3e-08), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1167-8T>C in individuals affected with Wilms Tumor, Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

GPC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	10
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs182950534; hg19: chrX-132826530;