rs148021273

Positions:

• chrX-133754155-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004484.4(GPC3):​c.359G>A​(p.Arg120His) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,163,014 control chromosomes in the GnomAD database, including 1 homozygotes. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., 10 hem., cov: 21)
  • Exomes 𝑓: 0.00011 (1 hom. 30 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.61

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027450472).
• BP6: Variant X-133754155-C-T is Benign according to our data. Variant chrX-133754155-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133754155-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.359G>A	p.Arg120His	missense_variant	3/8	ENST00000370818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.359G>A	p.Arg120His	missense_variant	3/8	1	NM_004484.4	P1

Frequencies

GnomAD3 genomes AF: 0.000536 AC: 54 AN: 100737 Hom.: 0 Cov.: 21 AF XY: 0.000387 AC XY: 10 AN XY: 25873

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00121

Gnomad SAS AF: 0.000460

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000398

Gnomad OTH AF: 0.00153

GnomAD3 exomes AF: 0.000313 AC: 54 AN: 172561 Hom.: 0 AF XY: 0.000281 AC XY: 17 AN XY: 60581

Gnomad AFR exome AF: 0.00180

Gnomad AMR exome AF: 0.0000766

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00159

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.000260

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 116 AN: 1062245 Hom.: 1 Cov.: 30 AF XY: 0.0000895 AC XY: 30 AN XY: 335055

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.000207

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000878

Gnomad4 SAS exome AF: 0.0000999

Gnomad4 FIN exome AF: 0.000226

Gnomad4 NFE exome AF: 0.0000123

Gnomad4 OTH exome AF: 0.000313

GnomAD4 genome AF: 0.000536 AC: 54 AN: 100769 Hom.: 0 Cov.: 21 AF XY: 0.000386 AC XY: 10 AN XY: 25913

Gnomad4 AFR AF: 0.00126

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00121

Gnomad4 SAS AF: 0.000463

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000398

Gnomad4 OTH AF: 0.00151

Alfa AF: 0.0000659 Hom.: 2

Bravo AF: 0.000759

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000297 AC: 36

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	This variant is associated with the following publications: (PMID: 28497333) -

GPC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 24, 2021

- -

Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.47
MVP		0.59
MPC		0.30
ClinPred		0.041	T
GERP RS		5.3
Varity_R		0.68
gMVP		0.66

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: rs148021273; hg19: chrX-132888182;