rs1556271627

Variant names:

• chrX-133699997-C-T
• rs1556271627
• NM_004484.4:c.1064G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The ENST00000370818.8(GPC3):​c.1064G>A​(p.Arg355His) variant causes a missense change. The variant allele was found at a frequency of 0.00000252 in 1,189,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: GPC3 ENST00000370818.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.49
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39073807).
• BP6: Variant X-133699997-C-T is Benign according to our data. Variant chrX-133699997-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543088.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370818.8. 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.1064G>A	p.Arg355His	missense	Exon 4 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.1133G>A	p.Arg378His	missense	Exon 5 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.1016G>A	p.Arg339His	missense	Exon 4 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.1064G>A	p.Arg355His	missense	Exon 4 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.1133G>A	p.Arg378His	missense	Exon 5 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.902G>A	p.Arg301His	missense	Exon 3 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111699 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1077932 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 344872

African (AFR) AF: 0.00 AC: 0 AN: 26026

American (AMR) AF: 0.00 AC: 0 AN: 34952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19218

East Asian (EAS) AF: 0.00 AC: 0 AN: 30084

South Asian (SAS) AF: 0.00 AC: 0 AN: 53091

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3978

European-Non Finnish (NFE) AF: 0.00000243 AC: 2 AN: 824683

Other (OTH) AF: 0.00 AC: 0 AN: 45425

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111747 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33989

African (AFR) AF: 0.0000324 AC: 1 AN: 30819

American (AMR) AF: 0.00 AC: 0 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2645

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5979

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53107

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Benign	0.052	T
Sift4G	Uncertain	0.042	D
Polyphen		0.83	P
Vest4		0.66
MVP		0.68
MPC		0.39
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.50
Mutation Taster		=58/42	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: rs1556271627; hg19: chrX-132834025; COSMIC: COSV63670124;