Genetic Variant NM_001448.3:c.1463A>G (chrX-133303171-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001448.3(GPC4):c.1463A>G(p.Asp488Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,209,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 0 hem. )

Consequence

GPC4
NM_001448.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

Publications

0 publications found

Variant links:

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

GPC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC4	NM_001448.3 link	c.1463A>G	p.Asp488Gly	missense_variant	Exon 8 of 9	ENST00000370828.4	NP_001439.2	O75487-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC4	ENST00000370828.4 link	c.1463A>G	p.Asp488Gly	missense_variant	Exon 8 of 9	1	NM_001448.3	ENSP00000359864.3		O75487-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112364

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000329

AC:

AN:

182200

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362760

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26388

American (AMR)

AF:

0.0000569

AC:

AN:

35178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19350

East Asian (EAS)

AF:

0.000166

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

53960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841597

Other (OTH)

AF:

0.00

AC:

AN:

46073

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112419

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34567

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30974

American (AMR)

AF:

0.00

AC:

AN:

10633

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.000281

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2707

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53310

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 06, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

-0.051

MutationAssessor

Uncertain

2.7

PhyloP100

4.6

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.64

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.43

MutPred

0.78

Loss of stability (P = 0.0301);

MVP

0.78

MPC

1.7

ClinPred

0.70

GERP RS

5.6

Varity_R

0.82

gMVP

0.75

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.61

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over