Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001129729.3(PLEKHG4):c.1235C>T(p.Thr412Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,318 control chromosomes in the GnomAD database, including 18,869 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.22 ( 7367 hom., cov: 32)

Exomes 𝑓: 0.092 ( 11502 hom. )

Consequence

PLEKHG4
NM_001129729.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.195

Publications

31 publications found

Variant links:

Genes affected

PLEKHG4 (HGNC:24501): (pleckstrin homology and RhoGEF domain containing G4) The protein encoded by this gene can function as a guanine nucleotide exchange factor (GEF) and may play a role in intracellular signaling and cytoskeleton dynamics at the Golgi apparatus. Polymorphisms in the region of this gene have been found to be associated with spinocerebellar ataxia in some study populations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

PLEKHG4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.3336244E-5).

BP6

Variant 16-67282331-C-T is Benign according to our data. Variant chr16-67282331-C-T is described in ClinVar as Benign. ClinVar VariationId is 129964.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129729.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG4	NM_001129729.3	MANE Select	c.1235C>T	p.Thr412Ile	missense	Exon 9 of 22	NP_001123201.1
PLEKHG4	NM_001129727.3		c.1235C>T	p.Thr412Ile	missense	Exon 10 of 23	NP_001123199.1
PLEKHG4	NM_001129728.2		c.1235C>T	p.Thr412Ile	missense	Exon 9 of 22	NP_001123200.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.1235C>T	p.Thr412Ile	missense	Exon 9 of 22	ENSP00000368649.3
PLEKHG4	ENST00000450733.5	TSL:1	c.992C>T	p.Thr331Ile	missense	Exon 7 of 20	ENSP00000398030.1
PLEKHG4	ENST00000393966.1	TSL:1	n.*741C>T		non_coding_transcript_exon	Exon 6 of 10	ENSP00000462601.1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33238

AN:

151984

Hom.:

7331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.571

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0605

Gnomad EAS

AF:

0.00484

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.185

Gnomad NFE

AF:

0.0740

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.118

AC:

29259

AN:

247982

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.582

Gnomad AMR exome

AF:

0.0660

Gnomad ASJ exome

AF:

0.0681

Gnomad EAS exome

AF:

0.00404

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.0787

Gnomad OTH exome

AF:

0.0957

GnomAD4 exome

AF:

0.0922

AC:

134694

AN:

1460216

Hom.:

11502

Cov.:

AF XY:

0.0921

AC XY:

66903

AN XY:

726364

show subpopulations

African (AFR)

AF:

0.594

AC:

19893

AN:

33462

American (AMR)

AF:

0.0696

AC:

3105

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.0703

AC:

1837

AN:

26126

East Asian (EAS)

AF:

0.00272

AC:

108

AN:

39678

South Asian (SAS)

AF:

0.144

AC:

12386

AN:

86214

European-Finnish (FIN)

AF:

0.140

AC:

7319

AN:

52300

Middle Eastern (MID)

AF:

0.152

AC:

878

AN:

5766

European-Non Finnish (NFE)

AF:

0.0741

AC:

82380

AN:

1111668

Other (OTH)

AF:

0.112

AC:

6788

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

7599

15198

22796

30395

37994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3294

6588

9882

13176

16470

<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:

0.219

AC:

33320

AN:

152102

Hom.:

7367

Cov.:

AF XY:

0.217

AC XY:

16161

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.571

AC:

23671

AN:

41452

American (AMR)

AF:

0.110

AC:

1674

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

210

AN:

3472

East Asian (EAS)

AF:

0.00485

AC:

AN:

5158

South Asian (SAS)

AF:

0.138

AC:

663

AN:

4818

European-Finnish (FIN)

AF:

0.148

AC:

1570

AN:

10612

Middle Eastern (MID)

AF:

0.178

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0740

AC:

5031

AN:

67992

Other (OTH)

AF:

0.167

AC:

353

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

941

1882

2823

3764

4705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.117

Hom.:

5312

Bravo

AF:

0.228

TwinsUK

AF:

0.0787

AC:

292

ALSPAC

AF:

0.0784

AC:

302

ESP6500AA

AF:

0.558

AC:

2454

ESP6500EA

AF:

0.0749

AC:

644

ExAC

AF:

0.129

AC:

15692

Asia WGS

AF:

0.122

AC:

424

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

Eigen

Benign

-0.079

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.58

MetaRNN

Benign

0.000043

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.20

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.2

REVEL

Benign

0.061

Sift

Benign

0.27

Sift4G

Benign

0.078

Polyphen

0.27

Vest4

0.057

MPC

0.29

ClinPred

0.017

GERP RS

3.2

Varity_R

0.036

gMVP

0.15

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over