chrX-133302997-T-C

Variant names:

• chrX-133302997-T-C
• rs927768064
• NM_001448.3:c.1541A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001448.3(GPC4):​c.1541A>G​(p.Asn514Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,209,563 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000018 (0 hom. 6 hem.)
• Consequence: GPC4 NM_001448.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.318
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0843972).
• BS2: High Hemizygotes in GnomAd4 at 2 XL,XLR gene

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.1541A>G	p.Asn514Ser	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.1541A>G	p.Asn514Ser	missense	Exon 9 of 9	ENSP00000359864.3	O75487-1
	GPC4	ENST00000887818.1		c.1541A>G	p.Asn514Ser	missense	Exon 10 of 10	ENSP00000557877.1
	GPC4	ENST00000931828.1		c.1541A>G	p.Asn514Ser	missense	Exon 10 of 10	ENSP00000601887.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111443 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183232 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 20 AN: 1098120 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 6 AN XY: 363476

African (AFR) AF: 0.0000379 AC: 1 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54146

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: 0.0000202 AC: 17 AN: 842011

Other (OTH) AF: 0.0000217 AC: 1 AN: 46096

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111443 Hom.: 0 Cov.: 23 AF XY: 0.0000595 AC XY: 2 AN XY: 33633

African (AFR) AF: 0.0000326 AC: 1 AN: 30641

American (AMR) AF: 0.00 AC: 0 AN: 10467

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53092

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.16
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.32
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.13
Sift	Benign	0.45	T
Sift4G	Benign	0.91	T
Polyphen		0.016	B
Vest4		0.22
MVP		0.18
MPC		0.45
ClinPred		0.056	T
GERP RS		5.6
Varity_R		0.066
gMVP		0.18
Mutation Taster		=87/13	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: rs927768064; hg19: chrX-132437025;