rs138450923

Variant names:

• chrX-133753854-G-A
• rs138450923
• NM_004484.4:c.660C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004484.4(GPC3):​c.660C>T​(p.Ser220Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000832 in 1,209,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 302 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00087 (0 hom. 291 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.472
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-133753854-G-A is Benign according to our data. Variant chrX-133753854-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239945.
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000474 (53/111835) while in subpopulation NFE AF = 0.000903 (48/53166). AF 95% confidence interval is 0.000699. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.660C>T	p.Ser220Ser	synonymous	Exon 3 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.660C>T	p.Ser220Ser	synonymous	Exon 3 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.612C>T	p.Ser204Ser	synonymous	Exon 3 of 8	NP_001158090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.660C>T	p.Ser220Ser	synonymous	Exon 3 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.660C>T	p.Ser220Ser	synonymous	Exon 3 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.498C>T	p.Ser166Ser	synonymous	Exon 2 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes AF: 0.000483 AC: 54 AN: 111782 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000163

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: 0.00424

Gnomad NFE AF: 0.000903

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000418 AC: 76 AN: 182012 AF XY: 0.000476

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000868 AC: 953 AN: 1097792 Hom.: 0 Cov.: 33 AF XY: 0.000801 AC XY: 291 AN XY: 363154

African (AFR) AF: 0.0000379 AC: 1 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00110 AC: 930 AN: 841700

Other (OTH) AF: 0.000456 AC: 21 AN: 46089

GnomAD4 genome AF: 0.000474 AC: 53 AN: 111835 Hom.: 0 Cov.: 23 AF XY: 0.000323 AC XY: 11 AN XY: 34043

African (AFR) AF: 0.000162 AC: 5 AN: 30775

American (AMR) AF: 0.00 AC: 0 AN: 10572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000903 AC: 48 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000430 Hom.: 5

Bravo AF: 0.000385

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	GPC3-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.3
DANN	Benign	0.56
PhyloP100		0.47
PromoterAI		-0.0091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs138450923; hg19: chrX-132887881;