NM_001448.3:c.1598G>C

Variant names:

• chrX-133302940-C-G
• rs148166792
• NM_001448.3:c.1598G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001448.3(GPC4):​c.1598G>C​(p.Arg533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R533C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: GPC4 NM_001448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058105588).

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.1598G>C	p.Arg533Pro	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.1598G>C	p.Arg533Pro	missense	Exon 9 of 9	ENSP00000359864.3	O75487-1
	GPC4	ENST00000887818.1		c.1598G>C	p.Arg533Pro	missense	Exon 10 of 10	ENSP00000557877.1
	GPC4	ENST00000931828.1		c.1598G>C	p.Arg533Pro	missense	Exon 10 of 10	ENSP00000601887.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.26
DANN	Benign	0.70
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.065
Sift	Benign	0.37	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.075
MutPred		0.47		Gain of helix (P = 0.0325)
MVP		0.043
MPC		0.79
ClinPred		0.039	T
GERP RS		-2.9
Varity_R		0.13
gMVP		0.43
Mutation Taster		=91/9	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: rs148166792; hg19: chrX-132436968; COSMIC: COSV100895478;