rs1048369

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001448.3(GPC4):c.1325C>T(p.Ala442Val) variant causes a missense change. The variant allele was found at a frequency of 0.312 in 1,206,963 control chromosomes in the GnomAD database, including 42,163 homozygotes. There are 125,172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 6635 hom., 11938 hem., cov: 22)

Exomes 𝑓: 0.31 ( 35528 hom. 113234 hem. )

Consequence

GPC4
NM_001448.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.92

Publications

26 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4469028E-4).

BP6

Variant X-133303309-G-A is Benign according to our data. Variant chrX-133303309-G-A is described in ClinVar as Benign. ClinVar VariationId is 1285303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC4	NM_001448.3 link	c.1325C>T	p.Ala442Val	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.1325C>T	p.Ala442Val	missense_variant	Exon 8 of 9	1	NM_001448.3	ENSP00000359864.3		O75487-1

Frequencies

GnomAD3 genomes

AF:

0.382

AC:

42064

AN:

110248

Hom.:

6633

Cov.:

show subpopulations

Gnomad AFR

AF:

0.594

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.369

Gnomad EAS

AF:

0.443

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.240

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.330

AC:

59799

AN:

181319

AF XY:

0.339

show subpopulations

Gnomad AFR exome

AF:

0.599

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.369

Gnomad EAS exome

AF:

0.444

Gnomad FIN exome

AF:

0.246

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.307

GnomAD4 exome

AF:

0.305

AC:

334730

AN:

1096658

Hom.:

35528

Cov.:

AF XY:

0.312

AC XY:

113234

AN XY:

362400

show subpopulations

African (AFR)

AF:

0.607

AC:

15993

AN:

26359

American (AMR)

AF:

0.187

AC:

6570

AN:

35102

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

7037

AN:

19366

East Asian (EAS)

AF:

0.399

AC:

12043

AN:

30189

South Asian (SAS)

AF:

0.498

AC:

26841

AN:

53922

European-Finnish (FIN)

AF:

0.255

AC:

10313

AN:

40470

Middle Eastern (MID)

AF:

0.372

AC:

1535

AN:

4125

European-Non Finnish (NFE)

AF:

0.284

AC:

238777

AN:

841087

Other (OTH)

AF:

0.339

AC:

15621

AN:

46038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

7633

15265

22898

30530

38163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8654

17308

25962

34616

43270

<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:

0.382

AC:

42091

AN:

110305

Hom.:

6635

Cov.:

AF XY:

0.366

AC XY:

11938

AN XY:

32587

show subpopulations

African (AFR)

AF:

0.594

AC:

17938

AN:

30223

American (AMR)

AF:

0.255

AC:

2652

AN:

10383

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

972

AN:

2633

East Asian (EAS)

AF:

0.443

AC:

1527

AN:

3448

South Asian (SAS)

AF:

0.492

AC:

1262

AN:

2566

European-Finnish (FIN)

AF:

0.240

AC:

1407

AN:

5863

Middle Eastern (MID)

AF:

0.322

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.293

AC:

15465

AN:

52796

Other (OTH)

AF:

0.367

AC:

552

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

866

1733

2599

3466

4332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.333

Hom.:

41285

Bravo

AF:

0.389

TwinsUK

AF:

0.276

AC:

1023

ALSPAC

AF:

0.288

AC:

831

ESP6500AA

AF:

0.597

AC:

2290

ESP6500EA

AF:

0.295

AC:

1986

ExAC

AF:

0.349

AC:

42354

EpiCase

AF:

0.301

EpiControl

AF:

0.299

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Keipert syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

MetaRNN

Benign

0.00014

MetaSVM

Benign

-0.91

MutationAssessor

Benign

2.0

PhyloP100

6.9

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.21

Sift

Benign

0.099

Sift4G

Benign

0.067

Polyphen

0.90

Vest4

0.063

MPC

1.5

ClinPred

0.030

GERP RS

4.7

Varity_R

0.15

gMVP

0.68

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over