X-133754159-C-G

Variant names:

• chrX-133754159-C-G
• rs1060502171
• NM_004484.4:c.355G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004484.4(GPC3):​c.355G>C​(p.Val119Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 932,393 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. V119F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000075 (0 hom. 5 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22598574).
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.355G>C	p.Val119Leu	missense	Exon 3 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.355G>C	p.Val119Leu	missense	Exon 3 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.307G>C	p.Val103Leu	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.355G>C	p.Val119Leu	missense	Exon 3 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.355G>C	p.Val119Leu	missense	Exon 3 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.193G>C	p.Val65Leu	missense	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000751 AC: 7 AN: 932393 Hom.: 0 Cov.: 29 AF XY: 0.0000183 AC XY: 5 AN XY: 272543

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22136

American (AMR) AF: 0.00 AC: 0 AN: 30312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17246

East Asian (EAS) AF: 0.00 AC: 0 AN: 27508

South Asian (SAS) AF: 0.0000242 AC: 1 AN: 41340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37633

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3484

European-Non Finnish (NFE) AF: 0.00000842 AC: 6 AN: 712868

Other (OTH) AF: 0.00 AC: 0 AN: 39866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.13
Sift	Benign	0.62	T
Sift4G	Benign	0.47	T
Polyphen		0.030	B
Vest4		0.20
MutPred		0.64		Loss of ubiquitination at K123 (P = 0.1498)
MVP		0.68
MPC		0.17
ClinPred		0.19	T
GERP RS		5.3
PromoterAI		-0.0014	Neutral
Varity_R		0.18
gMVP		0.75
Mutation Taster		=87/13	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: rs1060502171; hg19: chrX-132888186;