rs2314298

Variant names:

• chrX-133596513-A-G
• rs2314298
• NM_004484.4:c.1500T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004484.4(GPC3):​c.1500T>C​(p.Asp500Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,203,953 control chromosomes in the GnomAD database, including 1,127 homozygotes. There are 4,004 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (570 hom., 1822 hem., cov: 22)
  • Exomes 𝑓: 0.0074 (557 hom. 2182 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.89

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-133596513-A-G is Benign according to our data. Variant chrX-133596513-A-G is described in ClinVar as [Benign]. Clinvar id is 259405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1500T>C	p.Asp500Asp	synonymous_variant	Exon 7 of 8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1569T>C	p.Asp523Asp	synonymous_variant	Exon 8 of 9		NP_001158089.1
GPC3	NM_001164618.2	c.1452T>C	p.Asp484Asp	synonymous_variant	Exon 7 of 8		NP_001158090.1
GPC3	NM_001164619.2	c.1338T>C	p.Asp446Asp	synonymous_variant	Exon 6 of 7		NP_001158091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.1500T>C	p.Asp500Asp	synonymous_variant	Exon 7 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 6938 AN: 111568 Hom.: 567 Cov.: 22 AF XY: 0.0536 AC XY: 1808 AN XY: 33756

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.00717

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0192 AC: 3519 AN: 183229 Hom.: 283 AF XY: 0.0124 AC XY: 838 AN XY: 67761

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000918

Gnomad OTH exome AF: 0.00819

GnomAD4 exome AF: 0.00741 AC: 8092 AN: 1092330 Hom.: 557 Cov.: 29 AF XY: 0.00610 AC XY: 2182 AN XY: 357832

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.00672

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000463

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000697

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0624 AC: 6960 AN: 111623 Hom.: 570 Cov.: 22 AF XY: 0.0539 AC XY: 1822 AN XY: 33821

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.00717

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00114

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.0505

Alfa AF: 0.0327 Hom.: 396

Bravo AF: 0.0711

EpiCase AF: 0.00158

EpiControl AF: 0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GPC3 variant, c.1500T>C (p.Asp500Asp) causes a synonymous change involving a non-conserved nucleotide with / in silico programs via Alamut predicting no significant effect on splicing, 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 2082/87736 (1/42, 182 homozygotes, 453 hemizygotes), 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 and/or reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Simpson-Golabi-Behmel syndrome type 1 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Oct 12, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Feb 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.10
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs2314298; hg19: chrX-132730541;