NM_004484.4:c.1318G>A

Variant names:

• chrX-133661825-C-T
• rs1203009272
• NM_004484.4:c.1318G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP6

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.64
• Publications: 1 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 5 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543093.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1318G>A	p.Gly440Arg	missense_variant	Exon 6 of 8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1387G>A	p.Gly463Arg	missense_variant	Exon 7 of 9		NP_001158089.1
GPC3	NM_001164618.2	c.1270G>A	p.Gly424Arg	missense_variant	Exon 6 of 8		NP_001158090.1
GPC3	NM_001164619.2	c.1156G>A	p.Gly386Arg	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.1318G>A	p.Gly440Arg	missense_variant	Exon 6 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183470 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26156

American (AMR) AF: 0.0000284 AC: 1 AN: 35168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19263

East Asian (EAS) AF: 0.00 AC: 0 AN: 30113

South Asian (SAS) AF: 0.00 AC: 0 AN: 53812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40439

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4103

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828939

Other (OTH) AF: 0.00 AC: 0 AN: 45591

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wilms tumor 1 Benign:1

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.
PhyloP100		4.6
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
Mutation Taster		=66/34	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: rs1203009272; hg19: chrX-132795853;