X-133985356-CCGGCGG-CCGG

Variant names:

• chrX-133985356-CCGG-C
• rs749104500
• NM_004484.4:c.91_93delCCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_004484.4(GPC3):​c.91_93delCCG​(p.Pro31del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000736 in 1,086,915 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P31P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000074 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPC3 NM_004484.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.06
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004484.4
• BP6: Variant X-133985356-CCGG-C is Benign according to our data. Variant chrX-133985356-CCGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2347311.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 8	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111799 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000111 AC: 18 AN: 161907 AF XY: 0.0000187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000775

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000158

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.00000736 AC: 8 AN: 1086915 Hom.: 0 AF XY: 0.00000282 AC XY: 1 AN XY: 354847

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

African (AFR) AF: 0.0000382 AC: 1 AN: 26210

American (AMR) AF: 0.00 AC: 0 AN: 34530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19149

East Asian (EAS) AF: 0.00 AC: 0 AN: 29877

South Asian (SAS) AF: 0.0000760 AC: 4 AN: 52608

European-Finnish (FIN) AF: 0.0000255 AC: 1 AN: 39245

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4049

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 835656

Other (OTH) AF: 0.00 AC: 0 AN: 45591

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000002), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 111841 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34247

African (AFR) AF: 0.00 AC: 0 AN: 30885

American (AMR) AF: 0.00 AC: 0 AN: 10766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3451

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6119

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52843

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilms tumor 1 Uncertain:1

Jan 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with GPC3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.91_93del, results in the deletion of 1 amino acid(s) of the GPC3 protein (p.Pro31del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases Benign:1

Feb 25, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749104500; hg19: chrX-133119383; COSMIC: COSV105927708;