X-133754180-TAAAA-TAA

Position:

• chrX-133754180-TAAAA-TAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_004484.4(GPC3):​c.338-6_338-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 876,847 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.018 (0 hom. 1 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.240

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 -12 ACMG points.

• BP6: Variant X-133754180-TAA-T is Benign according to our data. Variant chrX-133754180-TAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 281155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133754180-TAA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0184 (14699/800453) while in subpopulation AMR AF= 0.037 (884/23880). AF 95% confidence interval is 0.035. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPC3	NM_004484.4	c.338-6_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.338-6_338-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004484.4	ENSP00000359854	P1

Frequencies

GnomAD3 genomes AF: 0.000249 AC: 19 AN: 76403 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 17813

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000553

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00249

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000185

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0184 AC: 14699 AN: 800453 Hom.: 0 AF XY: 0.00000455 AC XY: 1 AN XY: 219951

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.0370

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.00491

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.000249 AC: 19 AN: 76394 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 17822

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.000552

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00249

Gnomad4 NFE AF: 0.000185

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2017	- -
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)	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 16, 2015

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 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

Mar 23, 2020

- -

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;