X-133692376-C-T

Variant names:

• chrX-133692376-C-T
• rs11539789
• NM_004484.4:c.1285G>A

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.1285G>A​(p.Val429Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,210,255 control chromosomes in the GnomAD database, including 24 homozygotes. There are 1,849 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V429A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., 115 hem., cov: 24)
  • Exomes 𝑓: 0.0047 (21 hom. 1734 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 2.92
• Publications: 16 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 (MetaRNN=0.008226454).
• BP6: Variant X-133692376-C-T is Benign according to our data. Variant chrX-133692376-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00351 (397/113221) while in subpopulation AMR AF = 0.0104 (112/10747). AF 95% confidence interval is 0.00886. There are 3 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1285G>A	p.Val429Met	missense	Exon 5 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.1354G>A	p.Val452Met	missense	Exon 6 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.1237G>A	p.Val413Met	missense	Exon 5 of 8	NP_001158090.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1285G>A	p.Val429Met	missense	Exon 5 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.1354G>A	p.Val452Met	missense	Exon 6 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.1123G>A	p.Val375Met	missense	Exon 4 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 396 AN: 113168 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00338

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.00432

Gnomad FIN AF: 0.000476

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00328

GnomAD2 exomes AF: 0.00625 AC: 1146 AN: 183404 AF XY: 0.00587

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.00681

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.00817

GnomAD4 exome AF: 0.00469 AC: 5144 AN: 1097034 Hom.: 21 Cov.: 29 AF XY: 0.00478 AC XY: 1734 AN XY: 362442

African (AFR) AF: 0.00118 AC: 31 AN: 26378

American (AMR) AF: 0.0182 AC: 641 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00594 AC: 115 AN: 19373

East Asian (EAS) AF: 0.000861 AC: 26 AN: 30192

South Asian (SAS) AF: 0.00519 AC: 281 AN: 54111

European-Finnish (FIN) AF: 0.000568 AC: 23 AN: 40521

Middle Eastern (MID) AF: 0.00485 AC: 20 AN: 4127

European-Non Finnish (NFE) AF: 0.00452 AC: 3799 AN: 841088

Other (OTH) AF: 0.00452 AC: 208 AN: 46051

GnomAD4 genome AF: 0.00351 AC: 397 AN: 113221 Hom.: 3 Cov.: 24 AF XY: 0.00325 AC XY: 115 AN XY: 35367

African (AFR) AF: 0.00112 AC: 35 AN: 31254

American (AMR) AF: 0.0104 AC: 112 AN: 10747

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 9 AN: 2662

East Asian (EAS) AF: 0.00139 AC: 5 AN: 3610

South Asian (SAS) AF: 0.00434 AC: 12 AN: 2768

European-Finnish (FIN) AF: 0.000476 AC: 3 AN: 6303

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

European-Non Finnish (NFE) AF: 0.00404 AC: 216 AN: 53428

Other (OTH) AF: 0.00324 AC: 5 AN: 1545

Alfa AF: 0.00393 Hom.: 197

Bravo AF: 0.00436

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00372 AC: 25

ExAC AF: 0.00576 AC: 699

EpiCase AF: 0.00491

EpiControl AF: 0.00557

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (3)
-	-	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
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.010	D
Polyphen		0.43	B
Vest4		0.37
MVP		0.76
MPC		0.70
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.26
gMVP		0.59
Mutation Taster		=92/8	polymorphism (auto)

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: rs11539789; hg19: chrX-132826404; COSMIC: COSV104685937;