X-133754180-TAAAAAA-TAAAAA

Variant names:

• chrX-133754180-TA-T
• rs370737647
• NM_004484.4:c.338-5delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004484.4(GPC3):​c.338-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (247 hom., 1311 hem., cov: 19)
  • Exomes 𝑓: 0.21 (33 hom. 510 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.883
• 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 -16 ACMG points.

• BP6: Variant X-133754180-TA-T is Benign according to our data. Variant chrX-133754180-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004484.4. 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.338-5delT		splice_region intron	N/A	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.338-5delT		splice_region intron	N/A	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.290-5delT		splice_region intron	N/A	NP_001158090.1	B4DTD8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.338-5delT		splice_region intron	N/A	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.338-5delT		splice_region intron	N/A	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.176-5delT		splice_region intron	N/A	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.0827 AC: 6313 AN: 76327 Hom.: 244 Cov.: 19

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.0498

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.0352

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.386 AC: 27869 AN: 72176 AF XY: 0.0792

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.373

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.213 AC: 144462 AN: 679339 Hom.: 33 Cov.: 0 AF XY: 0.00415 AC XY: 510 AN XY: 122907

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

African (AFR) AF: 0.224 AC: 3651 AN: 16300

American (AMR) AF: 0.339 AC: 7015 AN: 20701

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 2686 AN: 12273

East Asian (EAS) AF: 0.243 AC: 4674 AN: 19209

South Asian (SAS) AF: 0.158 AC: 4583 AN: 29083

European-Finnish (FIN) AF: 0.251 AC: 5851 AN: 23287

Middle Eastern (MID) AF: 0.191 AC: 433 AN: 2267

European-Non Finnish (NFE) AF: 0.207 AC: 109034 AN: 527302

Other (OTH) AF: 0.226 AC: 6535 AN: 28917

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0828 AC: 6320 AN: 76318 Hom.: 247 Cov.: 19 AF XY: 0.0738 AC XY: 1311 AN XY: 17760

African (AFR) AF: 0.0765 AC: 1579 AN: 20628

American (AMR) AF: 0.255 AC: 1842 AN: 7230

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 66 AN: 1944

East Asian (EAS) AF: 0.0123 AC: 32 AN: 2597

South Asian (SAS) AF: 0.0262 AC: 44 AN: 1681

European-Finnish (FIN) AF: 0.0904 AC: 255 AN: 2820

Middle Eastern (MID) AF: 0.0403 AC: 5 AN: 124

European-Non Finnish (NFE) AF: 0.0626 AC: 2370 AN: 37834

Other (OTH) AF: 0.104 AC: 104 AN: 998

Alfa AF: 0.0768 Hom.: 71

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Wilms tumor 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
Mutation Taster		=100/0	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; COSMIC: COSV63658786; COSMIC: COSV63658786;