rs17000462

Variant names:

• chrX-133652718-A-G
• rs17000462
• NM_004484.4:c.1413+9012T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004484.4(GPC3):​c.1413+9012T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0475 in 111,864 control chromosomes in the GnomAD database, including 321 homozygotes. There are 1,412 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.047 (321 hom., 1412 hem., cov: 23)
• Consequence: GPC3 NM_004484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

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.1413+9012T>C		intron	N/A	NP_004475.1
	GPC3	NM_001164617.2		c.1482+9012T>C		intron	N/A	NP_001158089.1
	GPC3	NM_001164618.2		c.1365+9012T>C		intron	N/A	NP_001158090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1413+9012T>C		intron	N/A	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.1482+9012T>C		intron	N/A	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.1251+9012T>C		intron	N/A	ENSP00000486325.1

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 5288 AN: 111810 Hom.: 318 Cov.: 23

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.00717

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000748

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000807

Gnomad OTH AF: 0.0384

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0475 AC: 5313 AN: 111864 Hom.: 321 Cov.: 23 AF XY: 0.0415 AC XY: 1412 AN XY: 34022

African (AFR) AF: 0.162 AC: 4964 AN: 30655

American (AMR) AF: 0.0214 AC: 226 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00717 AC: 19 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.000750 AC: 2 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6107

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.000807 AC: 43 AN: 53258

Other (OTH) AF: 0.0379 AC: 58 AN: 1529

Alfa AF: 0.0406 Hom.: 180

Bravo AF: 0.0539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.54
DANN	Benign	0.78
PhyloP100		-0.30
Mutation Taster		=100/0	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: rs17000462; hg19: chrX-132786746;