NM_004484.4:c.337+21311T>C

Variant names:

• chrX-133931739-A-G
• rs1264379
• NM_004484.4:c.337+21311T>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.337+21311T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 111,578 control chromosomes in the GnomAD database, including 1,140 homozygotes. There are 5,042 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 0.14 (1140 hom., 5042 hem., cov: 22)
• Consequence: GPC3 NM_004484.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.337+21311T>C		intron_variant	Intron 2 of 7	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.337+21311T>C		intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 15956 AN: 111528 Hom.: 1137 Cov.: 22

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0672

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.143 AC: 15970 AN: 111578 Hom.: 1140 Cov.: 22 AF XY: 0.149 AC XY: 5042 AN XY: 33782

African (AFR) AF: 0.0854 AC: 2630 AN: 30792

American (AMR) AF: 0.361 AC: 3786 AN: 10500

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 244 AN: 2653

East Asian (EAS) AF: 0.430 AC: 1510 AN: 3515

South Asian (SAS) AF: 0.264 AC: 686 AN: 2598

European-Finnish (FIN) AF: 0.115 AC: 694 AN: 6022

Middle Eastern (MID) AF: 0.0553 AC: 12 AN: 217

European-Non Finnish (NFE) AF: 0.115 AC: 6080 AN: 53061

Other (OTH) AF: 0.157 AC: 241 AN: 1538

Alfa AF: 0.139 Hom.: 10799

Bravo AF: 0.167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.9
DANN	Benign	0.57
PhyloP100		-0.24
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: rs1264379; hg19: chrX-133065766;