X-133953167-A-C

Variant names:

• chrX-133953167-A-C
• rs1556359373
• NM_004484.4:c.220T>G

Variant summary

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

The NM_004484.4(GPC3):​c.220T>G​(p.Ser74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S74S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.220T>G	p.Ser74Ala	missense	Exon 2 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.220T>G	p.Ser74Ala	missense	Exon 2 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.220T>G	p.Ser74Ala	missense	Exon 2 of 8	NP_001158090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.220T>G	p.Ser74Ala	missense	Exon 2 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.220T>G	p.Ser74Ala	missense	Exon 2 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.175+32108T>G		intron	N/A	ENSP00000486325.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Uncertain:1

Sep 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces serine with alanine at codon 74 of the GPC3 protein (p.Ser74Ala). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GPC3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0").

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.034	D
Polyphen		0.56	P
Vest4		0.45
MutPred		0.80		Loss of disorder (P = 0.045)
MVP		0.85
MPC		2.1
ClinPred		0.80	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.87
Mutation Taster		=88/12	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: rs1556359373; hg19: chrX-133087194;