X-133754180-TAAAAAA-TAAA

Variant names:

• chrX-133754180-TAAA-T
• rs370737647
• NM_004484.4:c.338-7_338-5delTTT

Variant summary

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

The NM_004484.4(GPC3):​c.338-7_338-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 932,629 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 0.000026 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.0020 (0 hom. 0 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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-TAAA-T is Benign according to our data. Variant chrX-133754180-TAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 698976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Frequencies

GnomAD3 genomes AF: 0.0000261 AC: 2 AN: 76483 Hom.: 0 Cov.: 19

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: 0.000706

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00202 AC: 146 AN: 72176 AF XY: 0.00

Gnomad AFR exome AF: 0.000277

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.000496

Gnomad FIN exome AF: 0.00456

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000585

GnomAD4 exome AF: 0.00200 AC: 1713 AN: 856146 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 248268

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

African (AFR) AF: 0.00167 AC: 34 AN: 20308

American (AMR) AF: 0.00273 AC: 72 AN: 26341

Ashkenazi Jewish (ASJ) AF: 0.000656 AC: 11 AN: 16766

East Asian (EAS) AF: 0.000210 AC: 6 AN: 28609

South Asian (SAS) AF: 0.000897 AC: 39 AN: 43456

European-Finnish (FIN) AF: 0.000978 AC: 32 AN: 32707

Middle Eastern (MID) AF: 0.000985 AC: 3 AN: 3045

European-Non Finnish (NFE) AF: 0.00227 AC: 1468 AN: 647410

Other (OTH) AF: 0.00128 AC: 48 AN: 37504

⚠️ 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: 0.0000261 AC: 2 AN: 76483 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 17839

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

African (AFR) AF: 0.00 AC: 0 AN: 20618

American (AMR) AF: 0.00 AC: 0 AN: 7241

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: 1695

European-Finnish (FIN) AF: 0.000706 AC: 2 AN: 2832

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 37943

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00411 Hom.: 71

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (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		0.24
Mutation Taster		=81/19	polymorphism

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;