rs182950534

Variant names:

• chrX-133692502-A-G
• rs182950534
• NM_004484.4:c.1167-8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004484.4(GPC3):​c.1167-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,201,309 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,621 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., 96 hem., cov: 24)
  • Exomes 𝑓: 0.0045 (9 hom. 1525 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Scores: Splicing: ADA: 0.001398
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.690
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-133692502-A-G is Benign according to our data. Variant chrX-133692502-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00293 (330/112726) while in subpopulation NFE AF = 0.00441 (235/53347). AF 95% confidence interval is 0.00394. There are 2 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

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.1167-8T>C		splice_region intron	N/A	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.1236-8T>C		splice_region intron	N/A	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.1119-8T>C		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.1167-8T>C		splice_region intron	N/A	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.1236-8T>C		splice_region intron	N/A	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.1005-8T>C		splice_region intron	N/A	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 331 AN: 112673 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00129

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.00854

GnomAD2 exomes AF: 0.00251 AC: 458 AN: 182449 AF XY: 0.00243

Gnomad AFR exome AF: 0.000686

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00100

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00451 AC: 4907 AN: 1088583 Hom.: 9 Cov.: 27 AF XY: 0.00430 AC XY: 1525 AN XY: 354389

African (AFR) AF: 0.000839 AC: 22 AN: 26229

American (AMR) AF: 0.00293 AC: 103 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.000104 AC: 2 AN: 19308

East Asian (EAS) AF: 0.00 AC: 0 AN: 30114

South Asian (SAS) AF: 0.0000742 AC: 4 AN: 53898

European-Finnish (FIN) AF: 0.00111 AC: 45 AN: 40475

Middle Eastern (MID) AF: 0.00219 AC: 9 AN: 4104

European-Non Finnish (NFE) AF: 0.00545 AC: 4541 AN: 833513

Other (OTH) AF: 0.00395 AC: 181 AN: 45770

GnomAD4 genome AF: 0.00293 AC: 330 AN: 112726 Hom.: 2 Cov.: 24 AF XY: 0.00275 AC XY: 96 AN XY: 34862

African (AFR) AF: 0.000869 AC: 27 AN: 31080

American (AMR) AF: 0.00431 AC: 46 AN: 10666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3592

South Asian (SAS) AF: 0.00 AC: 0 AN: 2722

European-Finnish (FIN) AF: 0.00129 AC: 8 AN: 6214

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00441 AC: 235 AN: 53347

Other (OTH) AF: 0.00843 AC: 13 AN: 1542

Alfa AF: 0.00346 Hom.: 25

Bravo AF: 0.00327

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	GPC3-related disorder (1)
-	-	1	Hereditary ataxia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Intellectual disability (1)
-	-	1	Simpson-Golabi-Behmel syndrome type 1 (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.042
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: rs182950534; hg19: chrX-132826530;