X-133754180-TAAAA-TAAA

Position:

• chrX-133754180-TAAAA-TAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004484.4(GPC3):​c.338-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (247 hom., 1311 hem., cov: 19)
  • Exomes 𝑓: 0.21 (33 hom. 510 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.883

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.

• BP6: Variant X-133754180-TA-T is Benign according to our data. Variant chrX-133754180-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 218527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133754180-TA-T is described in Lovd as [Likely_benign]. Variant chrX-133754180-TA-T is described in Lovd as [Benign]. Variant chrX-133754180-TA-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4	c.338-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.338-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004484.4	ENSP00000359854	P1

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 6313 AN: 76327 Hom.: 244 Cov.: 19 AF XY: 0.0737 AC XY: 1308 AN XY: 17751

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.0498

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.0352

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.213 AC: 144462 AN: 679339 Hom.: 33 Cov.: 0 AF XY: 0.00415 AC XY: 510 AN XY: 122907

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.243

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.0828 AC: 6320 AN: 76318 Hom.: 247 Cov.: 19 AF XY: 0.0738 AC XY: 1311 AN XY: 17760

Gnomad4 AFR AF: 0.0765

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.0262

Gnomad4 FIN AF: 0.0904

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Present in 32% of Europeans in ExAC, but fails inbreeding coefficient filter. Not predicted to impact splicing. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Wilms tumor 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 09, 2019

- -

Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs370737647; hg19: chrX-132888207;