chrX-133536241-T-C

Position:

• chrX-133536241-T-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.1626A>G​(p.Ala542Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,201,163 control chromosomes in the GnomAD database, including 837 homozygotes. There are 3,145 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (417 hom., 1428 hem., cov: 20)
  • Exomes 𝑓: 0.0060 (420 hom. 1717 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.239

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-133536241-T-C is Benign according to our data. Variant chrX-133536241-T-C is described in ClinVar as [Benign]. Clinvar id is 137490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.239 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1626A>G	p.Ala542Ala	synonymous_variant	8/8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1695A>G	p.Ala565Ala	synonymous_variant	9/9		NP_001158089.1
GPC3	NM_001164618.2	c.1578A>G	p.Ala526Ala	synonymous_variant	8/8		NP_001158090.1
GPC3	NM_001164619.2	c.1464A>G	p.Ala488Ala	synonymous_variant	7/7		NP_001158091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.1626A>G	p.Ala542Ala	synonymous_variant	8/8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 5803 AN: 109415 Hom.: 415 Cov.: 20 AF XY: 0.0447 AC XY: 1416 AN XY: 31709

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00686

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000806

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000607

Gnomad OTH AF: 0.0439

GnomAD3 exomes AF: 0.0163 AC: 2981 AN: 182961 Hom.: 219 AF XY: 0.0103 AC XY: 694 AN XY: 67551

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.00831

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00601 AC: 6564 AN: 1091692 Hom.: 420 Cov.: 30 AF XY: 0.00481 AC XY: 1717 AN XY: 357228

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.00991

Gnomad4 ASJ exome AF: 0.00672

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000333

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0532 AC: 5819 AN: 109471 Hom.: 417 Cov.: 20 AF XY: 0.0449 AC XY: 1428 AN XY: 31775

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00686

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000808

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000607

Gnomad4 OTH AF: 0.0433

Alfa AF: 0.0282 Hom.: 163

Bravo AF: 0.0613

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

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.1626A>G (p.Ala542Ala) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico tools 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 1792/87714 (1/48, 141 homozygotes, 396 hemizygotes), which significantly exceeds the estimated maxium 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. A reputable clinical laboratory cites the variant as "benign." Therefore, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Oct 12, 2015

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 24, 2020

- -

Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs61754631; hg19: chrX-132670269;