NM_004484.4:c.955G>T

Variant names:

• chrX-133753559-C-A
• rs753020197
• NM_004484.4:c.955G>T

Variant summary

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

The NM_004484.4(GPC3):​c.955G>T​(p.Val319Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,482 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V319I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.955G>T	p.Val319Leu	missense	Exon 3 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.955G>T	p.Val319Leu	missense	Exon 3 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.907G>T	p.Val303Leu	missense	Exon 3 of 8	NP_001158090.1	B4DTD8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.955G>T	p.Val319Leu	missense	Exon 3 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.955G>T	p.Val319Leu	missense	Exon 3 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.793G>T	p.Val265Leu	missense	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095482 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360886

African (AFR) AF: 0.00 AC: 0 AN: 26350

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839618

Other (OTH) AF: 0.00 AC: 0 AN: 46006

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.057	B
Vest4		0.57
MutPred		0.54		Loss of catalytic residue at V319 (P = 0.2111)
MVP		0.60
MPC		0.20
ClinPred		0.75	D
GERP RS		2.7
PromoterAI		0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.80
Mutation Taster		=59/41	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: rs753020197; hg19: chrX-132887586; COSMIC: COSV63669721;