chrX-133536125-C-A

Variant names:

• chrX-133536125-C-A
• NM_004484.4:c.1742G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_004484.4(GPC3):​c.1742G>T​(p.Ter581Leuext*?) variant causes a stop lost 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 (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: GPC3 NM_004484.4 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.68
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_004484.4 Downstream stopcodon found after 1 codons.

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.1742G>T	p.Ter581Leuext*?	stop_lost	Exon 8 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.1811G>T	p.Ter604Leuext*?	stop_lost	Exon 9 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.1694G>T	p.Ter565Leuext*?	stop_lost	Exon 8 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.1742G>T	p.Ter581Leuext*?	stop_lost	Exon 8 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.1811G>T	p.Ter604Leuext*?	stop_lost	Exon 9 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.1580G>T	p.Ter527Leuext*?	stop_lost splice_region	Exon 7 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Benign	0.84
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		2.7
Vest4		0.23
GERP RS		5.1
Mutation Taster		=53/147	disease causing

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

hg19: chrX-132670153;