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_001164617.2(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_001164617.2 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_001164617.2
• 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 VariationId is 2347311.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164617.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 8	NP_001158090.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.91_93delCCG	p.Pro31del	conservative_inframe_deletion	Exon 1 of 7	ENSP00000486325.1

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 = 0.00000209599), 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

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;