chrX-133303048-C-A

Variant names:

• chrX-133303048-C-A
• NM_001448.3:c.1490G>T

Variant summary

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

The NM_001448.3(GPC4):​c.1490G>T​(p.Gly497Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,970 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: GPC4 NM_001448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.677
• Publications: 0 publications found

Genes affected

GPC4 (HGNC:4452): (glypican 4) 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 GPC4 gene is adjacent to the 3' end of GPC3 and may also play a role in Simpson-Golabi-Behmel syndrome. [provided by RefSeq, Jul 2008]

GPC4 Gene-Disease associations (from GenCC):

• Keipert syndrome

  Inheritance: XLR, XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001448.3. 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
	GPC4	NM_001448.3	MANE Select	c.1490G>T	p.Gly497Val	missense	Exon 9 of 9	NP_001439.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC4	ENST00000370828.4	TSL:1 MANE Select	c.1490G>T	p.Gly497Val	missense	Exon 9 of 9	ENSP00000359864.3	O75487-1
	GPC4	ENST00000887818.1		c.1490G>T	p.Gly497Val	missense	Exon 10 of 10	ENSP00000557877.1
	GPC4	ENST00000931828.1		c.1490G>T	p.Gly497Val	missense	Exon 10 of 10	ENSP00000601887.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097970 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363330

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841888

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0071	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.68
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.77		Loss of phosphorylation at S500 (P = 0.201)
MVP		0.59
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.82
gMVP		0.71
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chrX-132437076;