chrX-133985370-G-A

Variant names:

• chrX-133985370-G-A
• rs1556367809
• NM_004484.4:c.80C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004484.4(GPC3):​c.80C>T​(p.Pro27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,087,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29
• 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=0.17421463).

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.80C>T	p.Pro27Leu	missense	Exon 1 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.80C>T	p.Pro27Leu	missense	Exon 1 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.80C>T	p.Pro27Leu	missense	Exon 1 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.80C>T	p.Pro27Leu	missense	Exon 1 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.80C>T	p.Pro27Leu	missense	Exon 1 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.80C>T	p.Pro27Leu	missense	Exon 1 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1087062 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 1 AN XY: 354840

African (AFR) AF: 0.00 AC: 0 AN: 26231

American (AMR) AF: 0.00 AC: 0 AN: 34176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19145

East Asian (EAS) AF: 0.00 AC: 0 AN: 29754

South Asian (SAS) AF: 0.0000381 AC: 2 AN: 52498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4031

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836691

Other (OTH) AF: 0.00 AC: 0 AN: 45616

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Uncertain:1

Feb 14, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 27 of the GPC3 protein (p.Pro27Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 543086). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.30	T
Polyphen		0.012	B
Vest4		0.27
MutPred		0.46		Loss of glycosylation at P27 (P = 0.0016)
MVP		0.61
MPC		1.7
ClinPred		0.34	T
GERP RS		3.0
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.16
gMVP		0.37
Mutation Taster		=92/8	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: rs1556367809; hg19: chrX-133119397;