X-133754180-TAAAAAA-TAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_004484.4(GPC3):​c.338-6_338-5delTT variant causes a splice region, 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, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.240
• Publications: 7 publications found

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]

GPC3 Gene-Disease associations (from GenCC):

• Simpson-Golabi-Behmel syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Simpson-Golabi-Behmel syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant X-133754180-TAA-T is Benign according to our data. Variant chrX-133754180-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.338-6_338-5delTT		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.338-6_338-5delTT		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3

Frequencies

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

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

GnomAD2 exomes AF: 0.0263 AC: 1899 AN: 72176 AF XY: 0.00

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0583

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.0174

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0292

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0155 AC: 296 AN: 19067

American (AMR) AF: 0.0370 AC: 884 AN: 23880

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 223 AN: 15513

East Asian (EAS) AF: 0.00491 AC: 129 AN: 26276

South Asian (SAS) AF: 0.0108 AC: 425 AN: 39460

European-Finnish (FIN) AF: 0.0110 AC: 330 AN: 30072

Middle Eastern (MID) AF: 0.00854 AC: 24 AN: 2809

European-Non Finnish (NFE) AF: 0.0195 AC: 11840 AN: 608546

Other (OTH) AF: 0.0157 AC: 548 AN: 34830

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000485 AC: 1 AN: 20637

American (AMR) AF: 0.000552 AC: 4 AN: 7240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1942

East Asian (EAS) AF: 0.00 AC: 0 AN: 2599

South Asian (SAS) AF: 0.00 AC: 0 AN: 1681

European-Finnish (FIN) AF: 0.00249 AC: 7 AN: 2808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.000185 AC: 7 AN: 37902

Other (OTH) AF: 0.00 AC: 0 AN: 1001

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0166 Hom.: 71

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Jun 16, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 03, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 23, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs370737647; hg19: chrX-132888207;