chrX-133754180-T-TAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_004484.4(GPC3):​c.338-6_338-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., 1 hem., cov: 19)
  • Exomes 𝑓: 0.0024 (0 hom. 0 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -12 ACMG points.

• BP6: Variant X-133754180-T-TAA is Benign according to our data. Variant chrX-133754180-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1692814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000654 (5/76495) while in subpopulation AFR AF = 0.000146 (3/20618). AF 95% confidence interval is 0.0000395. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

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.338-6_338-5dupTT		splice_region intron	N/A	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.338-6_338-5dupTT		splice_region intron	N/A	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.290-6_290-5dupTT		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.338-5_338-4insTT		splice_region intron	N/A	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.338-5_338-4insTT		splice_region intron	N/A	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.176-5_176-4insTT		splice_region intron	N/A	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.0000654 AC: 5 AN: 76495 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000146

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: 0.0000527

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00310 AC: 224 AN: 72176 AF XY: 0.00

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00534

Gnomad EAS exome AF: 0.00314

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00240 AC: 2057 AN: 858102 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 249560

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

African (AFR) AF: 0.00291 AC: 59 AN: 20258

American (AMR) AF: 0.000789 AC: 21 AN: 26600

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 41 AN: 16834

East Asian (EAS) AF: 0.000838 AC: 24 AN: 28647

South Asian (SAS) AF: 0.00138 AC: 60 AN: 43480

European-Finnish (FIN) AF: 0.000972 AC: 32 AN: 32906

Middle Eastern (MID) AF: 0.00262 AC: 8 AN: 3049

European-Non Finnish (NFE) AF: 0.00269 AC: 1747 AN: 648753

Other (OTH) AF: 0.00173 AC: 65 AN: 37575

⚠️ 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: 0.0000654 AC: 5 AN: 76495 Hom.: 0 Cov.: 19 AF XY: 0.0000560 AC XY: 1 AN XY: 17847

African (AFR) AF: 0.000146 AC: 3 AN: 20618

American (AMR) AF: 0.00 AC: 0 AN: 7242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1948

East Asian (EAS) AF: 0.00 AC: 0 AN: 2611

South Asian (SAS) AF: 0.00 AC: 0 AN: 1693

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2839

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.0000527 AC: 2 AN: 37949

Other (OTH) AF: 0.00 AC: 0 AN: 991

Alfa AF: 0.00262 Hom.: 71

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	GPC3-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (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		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370737647; hg19: chrX-132888207;