rs1015207544

Variant names:

• chrX-133596445-A-G
• rs1015207544
• NM_004484.4:c.1568T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004484.4(GPC3):​c.1568T>C​(p.Leu523Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 1,206,276 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.34

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1568T>C	p.Leu523Pro	missense_variant	Exon 7 of 8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1637T>C	p.Leu546Pro	missense_variant	Exon 8 of 9		NP_001158089.1
GPC3	NM_001164618.2	c.1520T>C	p.Leu507Pro	missense_variant	Exon 7 of 8		NP_001158090.1
GPC3	NM_001164619.2	c.1406T>C	p.Leu469Pro	missense_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.1568T>C	p.Leu523Pro	missense_variant	Exon 7 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112057 Hom.: 0 Cov.: 23 AF XY: 0.0000585 AC XY: 2 AN XY: 34215

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1094219 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1 AN XY: 359731

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000716

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112057 Hom.: 0 Cov.: 23 AF XY: 0.0000585 AC XY: 2 AN XY: 34215

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilms tumor 1 Uncertain:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 523 of the GPC3 protein (p.Leu523Pro). This variant is present in population databases (no rsID available, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 543089). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 Uncertain:1

Feb 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.56
MutPred		0.84		Loss of helix (P = 0.0017);.;.;
MVP		0.87
MPC		0.93
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.82
gMVP		0.73

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: rs1015207544; hg19: chrX-132730473;