rs1203009272

chrX-133661825-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM2 PP3_Strong BP6_Moderate

The NM_004484.4(GPC3):c.1318G>A(p.Gly440Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000923 in 1,083,584 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.64

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• BP6: Variant X-133661825-C-T is Benign according to our data. Variant chrX-133661825-C-T is described in ClinVar as [Benign]. Clinvar id is 543093.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.1318G>A	p.Gly440Arg	missense_variant	6/8	ENST00000370818.8
GPC3	NM_001164617.2	c.1387G>A	p.Gly463Arg	missense_variant	7/9
GPC3	NM_001164618.2	c.1270G>A	p.Gly424Arg	missense_variant	6/8
GPC3	NM_001164619.2	c.1156G>A	p.Gly386Arg	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.1318G>A	p.Gly440Arg	missense_variant	6/8	1	NM_004484.4	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183470 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67918

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083584 Hom.: 0 Cov.: 27 AF XY: 0.00000286 AC XY: 1 AN XY: 349538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;.;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	D;D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.80		Gain of solvent accessibility (P = 0.0171);.;.;
MVP		0.86
MPC		0.72
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.85

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: rs1203009272; hg19: chrX-132795853;