rs104894854

Variant names:

• chrX-133753628-A-T
• rs104894854
• NM_004484.4:c.886T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004484.4(GPC3):​c.886T>A​(p.Trp296Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.87

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-133753628-A-T is Pathogenic according to our data. Variant chrX-133753628-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11687.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.886T>A	p.Trp296Arg	missense_variant	Exon 3 of 8	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.886T>A	p.Trp296Arg	missense_variant	Exon 3 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Simpson-Golabi-Behmel syndrome type 1 Pathogenic:1

May 22, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-14	D;D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.92		Gain of methylation at K294 (P = 0.0739);Gain of methylation at K294 (P = 0.0739);.;
MVP		1.0
MPC		0.97
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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: rs104894854; hg19: chrX-132887655;