X-133953183-C-T

Variant names:

• chrX-133953183-C-T
• rs61754632
• NM_004484.4:c.204G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004484.4(GPC3):​c.204G>A​(p.Lys68Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,207,011 control chromosomes in the GnomAD database, including 31 homozygotes. There are 597 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., 289 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (9 hom. 308 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.91
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-133953183-C-T is Benign according to our data. Variant chrX-133953183-C-T is described in ClinVar as Benign. ClinVar VariationId is 415272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1191/110530) while in subpopulation AFR AF = 0.0363 (1103/30350). AF 95% confidence interval is 0.0346. There are 22 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.204G>A	p.Lys68Lys	synonymous	Exon 2 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.204G>A	p.Lys68Lys	synonymous	Exon 2 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.204G>A	p.Lys68Lys	synonymous	Exon 2 of 8	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.204G>A	p.Lys68Lys	synonymous	Exon 2 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.204G>A	p.Lys68Lys	synonymous	Exon 2 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.175+32092G>A		intron	N/A	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1195 AN: 110476 Hom.: 22 Cov.: 23

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00851

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.0102

GnomAD2 exomes AF: 0.00301 AC: 552 AN: 183118 AF XY: 0.00205

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00113 AC: 1235 AN: 1096481 Hom.: 9 Cov.: 30 AF XY: 0.000851 AC XY: 308 AN XY: 361857

African (AFR) AF: 0.0356 AC: 938 AN: 26375

American (AMR) AF: 0.00205 AC: 72 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40483

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4134

European-Non Finnish (NFE) AF: 0.0000952 AC: 80 AN: 840559

Other (OTH) AF: 0.00293 AC: 135 AN: 46036

GnomAD4 genome AF: 0.0108 AC: 1191 AN: 110530 Hom.: 22 Cov.: 23 AF XY: 0.00882 AC XY: 289 AN XY: 32778

African (AFR) AF: 0.0363 AC: 1103 AN: 30350

American (AMR) AF: 0.00661 AC: 68 AN: 10283

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3517

South Asian (SAS) AF: 0.00 AC: 0 AN: 2548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5840

Middle Eastern (MID) AF: 0.00469 AC: 1 AN: 213

European-Non Finnish (NFE) AF: 0.0000755 AC: 4 AN: 52978

Other (OTH) AF: 0.0101 AC: 15 AN: 1489

Alfa AF: 0.00540 Hom.: 26

Bravo AF: 0.0123

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	GPC3-related disorder (1)
-	-	1	Inborn genetic diseases (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	-0.37
CADD	Benign	9.8
DANN	Benign	0.69
PhyloP100		1.9
Mutation Taster		=94/6	polymorphism (auto)

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: rs61754632; hg19: chrX-133087210;