rs398124166

Variant names:

• chrX-133985279-C-T
• rs398124166
• NM_004484.4:c.171G>A
• GPC3 p.Val57Val

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004484.4(GPC3):​c.171G>A​(p.Val57Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,209,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000091 (0 hom. 3 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.689
• 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: ClinGen, Orphanet
• Simpson-Golabi-Behmel syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-133985279-C-T is Benign according to our data. Variant chrX-133985279-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95099.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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.171G>A	p.Val57Val	synonymous	Exon 1 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.171G>A	p.Val57Val	synonymous	Exon 1 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.171G>A	p.Val57Val	synonymous	Exon 1 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.171G>A	p.Val57Val	synonymous	Exon 1 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.171G>A	p.Val57Val	synonymous	Exon 1 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.171G>A	p.Val57Val	synonymous	Exon 1 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112799 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 178032 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000912 AC: 10 AN: 1096999 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 3 AN XY: 362605

African (AFR) AF: 0.00 AC: 0 AN: 26373

American (AMR) AF: 0.00 AC: 0 AN: 35155

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 53925

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4077

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841560

Other (OTH) AF: 0.00 AC: 0 AN: 46023

GnomAD4 genome AF: 0.00000887 AC: 1 AN: 112799 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34967

African (AFR) AF: 0.00 AC: 0 AN: 31061

American (AMR) AF: 0.00 AC: 0 AN: 10803

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2767

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6281

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53252

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.5
DANN	Benign	0.94
PhyloP100		0.69
PromoterAI		0.0092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398124166;

hg19: chrX-133119306;