rs751413609

Positions:

• chrX-133536296-GTCAA-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_004484.4(GPC3):​c.1574-7_1574-4del 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 0.000674 in 1,190,583 control chromosomes in the GnomAD database, including 1 homozygotes. There are 257 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 0.00049 (0 hom., 18 hem., cov: 20)
  • Exomes 𝑓: 0.00069 (1 hom. 239 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.42

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-133536296-GTCAA-G is Benign according to our data. Variant chrX-133536296-GTCAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 239939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133536296-GTCAA-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.1574-7_1574-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370818.8
GPC3	NM_001164617.2	c.1643-7_1643-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
GPC3	NM_001164618.2	c.1526-7_1526-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
GPC3	NM_001164619.2	c.1412-7_1412-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.1574-7_1574-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004484.4	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 54 AN: 111219 Hom.: 0 Cov.: 20 AF XY: 0.000539 AC XY: 18 AN XY: 33395

Gnomad AFR AF: 0.0000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.000385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000905

Gnomad OTH AF: 0.000670

GnomAD3 exomes AF: 0.000666 AC: 121 AN: 181817 Hom.: 0 AF XY: 0.000865 AC XY: 58 AN XY: 67047

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000472

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000693 AC: 748 AN: 1079310 Hom.: 1 AF XY: 0.000690 AC XY: 239 AN XY: 346236

Gnomad4 AFR exome AF: 0.000192

Gnomad4 AMR exome AF: 0.0000853

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.0000987

Gnomad4 NFE exome AF: 0.000826

Gnomad4 OTH exome AF: 0.000550

GnomAD4 genome AF: 0.000485 AC: 54 AN: 111273 Hom.: 0 Cov.: 20 AF XY: 0.000538 AC XY: 18 AN XY: 33459

Gnomad4 AFR AF: 0.0000979

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.000386

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000905

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.000545 Hom.: 5

Bravo AF: 0.000563

EpiCase AF: 0.00191

EpiControl AF: 0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2018

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 07, 2021

- -

Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

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: rs751413609; hg19: chrX-132670324;