chrX-133692376-C-A

Variant names:

• chrX-133692376-C-A
• rs11539789
• NM_004484.4:c.1285G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004484.4(GPC3):​c.1285G>T​(p.Val429Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,045 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V429A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1285G>T	p.Val429Leu	missense_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.1285G>T	p.Val429Leu	missense_variant	Exon 5 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097045 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362443

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841095

Other (OTH) AF: 0.0000217 AC: 1 AN: 46051

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.055	T;D;.
Sift4G	Benign	0.091	T;T;T
Polyphen		0.057	B;.;.
Vest4		0.68
MutPred		0.60		Gain of helix (P = 0.062);.;.;
MVP		0.65
MPC		0.52
ClinPred		0.79	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.64
Mutation Taster		=87/13	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: rs11539789; hg19: chrX-132826404;