X-133754180-TAAAAAA-TAAAAAAAA

Variant names:

• chrX-133754180-T-TAA
• rs370737647
• NM_004484.4:c.338-6_338-5dupTT

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_338-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., 1 hem., cov: 19)
  • Exomes 𝑓: 0.0024 (0 hom. 0 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -12 ACMG points.

• BP6: Variant X-133754180-T-TAA is Benign according to our data. Variant chrX-133754180-T-TAA is described in ClinVar as [Likely_benign]. Clinvar id is 1692814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000654 (5/76495) while in subpopulation AFR AF= 0.000146 (3/20618). AF 95% confidence interval is 0.0000395. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.338-6_338-5dupTT		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.338-5_338-4insTT		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.0000654 AC: 5 AN: 76495 Hom.: 0 Cov.: 19 AF XY: 0.0000560 AC XY: 1 AN XY: 17847

Gnomad AFR AF: 0.000146

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: 0.0000527

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00240 AC: 2057 AN: 858102 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 249560

Gnomad4 AFR exome AF: 0.00291

Gnomad4 AMR exome AF: 0.000789

Gnomad4 ASJ exome AF: 0.00244

Gnomad4 EAS exome AF: 0.000838

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.000972

Gnomad4 NFE exome AF: 0.00269

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.0000654 AC: 5 AN: 76495 Hom.: 0 Cov.: 19 AF XY: 0.0000560 AC XY: 1 AN XY: 17847

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000527

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GPC3-related disorder Benign:1

Aug 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Jul 21, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

Dec 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;