rs756598026

Variant names:

• chrX-133692374-C-T
• rs756598026
• NM_004484.4:c.1287G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_004484.4(GPC3):​c.1287G>A​(p.Val429Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,210,091 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000026 (0 hom. 13 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.894
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-133692374-C-T is Benign according to our data. Variant chrX-133692374-C-T is described in ClinVar as [Benign]. Clinvar id is 476645.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.894 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000619 (7/113156) while in subpopulation NFE AF = 0.0000936 (5/53415). AF 95% confidence interval is 0.0000368. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1287G>A	p.Val429Val	synonymous_variant	Exon 5 of 8	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.1287G>A	p.Val429Val	synonymous_variant	Exon 5 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.0000619 AC: 7 AN: 113102 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000932

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000936

Gnomad OTH AF: 0.000658

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183412 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 28 AN: 1096935 Hom.: 0 Cov.: 29 AF XY: 0.0000359 AC XY: 13 AN XY: 362339

African (AFR) AF: 0.00 AC: 0 AN: 26375

American (AMR) AF: 0.0000284 AC: 1 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.0000262 AC: 22 AN: 840982

Other (OTH) AF: 0.000109 AC: 5 AN: 46056

GnomAD4 genome AF: 0.0000619 AC: 7 AN: 113156 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35302

African (AFR) AF: 0.00 AC: 0 AN: 31250

American (AMR) AF: 0.0000931 AC: 1 AN: 10743

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2665

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2763

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6275

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000936 AC: 5 AN: 53415

Other (OTH) AF: 0.000650 AC: 1 AN: 1539

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.9
DANN	Benign	0.74
PhyloP100		0.89
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs756598026; hg19: chrX-132826402;