chrX-133661734-T-C

Variant names:

• chrX-133661734-T-C
• rs1556233454
• NM_004484.4:c.1409A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004484.4(GPC3):​c.1409A>G​(p.Asn470Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N470K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40235856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1409A>G	p.Asn470Ser	missense_variant	Exon 6 of 8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1478A>G	p.Asn493Ser	missense_variant	Exon 7 of 9		NP_001158089.1
GPC3	NM_001164618.2	c.1361A>G	p.Asn454Ser	missense_variant	Exon 6 of 8		NP_001158090.1
GPC3	NM_001164619.2	c.1247A>G	p.Asn416Ser	missense_variant	Exon 5 of 7		NP_001158091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.1409A>G	p.Asn470Ser	missense_variant	Exon 6 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1039029 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 317601

African (AFR) AF: 0.00 AC: 0 AN: 25312

American (AMR) AF: 0.00 AC: 0 AN: 34851

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18719

East Asian (EAS) AF: 0.00 AC: 0 AN: 29340

South Asian (SAS) AF: 0.00 AC: 0 AN: 52843

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3976

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 790546

Other (OTH) AF: 0.00 AC: 0 AN: 43812

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Uncertain:1

Aug 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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"). 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 variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 470 of the GPC3 protein (p.Asn470Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		4.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.17	T;T;.
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.50
MutPred		0.50		Gain of disorder (P = 0.0748);.;.;
MVP		0.82
MPC		0.31
ClinPred		0.88	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.58
Mutation Taster		=84/16	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: rs1556233454; hg19: chrX-132795762;