chr16-67284339-A-G

Variant names:

Variant summary

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

The NM_001129729.3(PLEKHG4):c.1574A>G(p.Asp525Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,146 control chromosomes in the GnomAD database, including 26,330 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.26 ( 9185 hom., cov: 32)

Exomes 𝑓: 0.12 ( 17145 hom. )

Consequence

PLEKHG4
NM_001129729.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.793

Publications

36 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=3.837583E-6).

BP6

Variant 16-67284339-A-G is Benign according to our data. Variant chr16-67284339-A-G is described in ClinVar as Benign. ClinVar VariationId is 129965.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 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.1574A>G	p.Asp525Gly	missense	Exon 12 of 22	NP_001123201.1
PLEKHG4	NM_001129727.3		c.1574A>G	p.Asp525Gly	missense	Exon 13 of 23	NP_001123199.1
PLEKHG4	NM_001129728.2		c.1574A>G	p.Asp525Gly	missense	Exon 12 of 22	NP_001123200.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.1574A>G	p.Asp525Gly	missense	Exon 12 of 22	ENSP00000368649.3
PLEKHG4	ENST00000450733.5	TSL:1	c.1331A>G	p.Asp444Gly	missense	Exon 10 of 20	ENSP00000398030.1
PLEKHG4	ENST00000393966.1	TSL:1	n.*1080A>G		non_coding_transcript_exon	Exon 9 of 10	ENSP00000462601.1

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38823

AN:

151600

Hom.:

9144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.0748

Gnomad EAS

AF:

0.0309

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.149

AC:

37172

AN:

248826

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.637

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.0869

Gnomad EAS exome

AF:

0.0237

Gnomad FIN exome

AF:

0.150

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.124

AC:

181773

AN:

1461428

Hom.:

17145

Cov.:

AF XY:

0.124

AC XY:

90070

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.654

AC:

21897

AN:

33464

American (AMR)

AF:

0.114

AC:

5111

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0881

AC:

2302

AN:

26126

East Asian (EAS)

AF:

0.0220

AC:

872

AN:

39694

South Asian (SAS)

AF:

0.173

AC:

14904

AN:

86240

European-Finnish (FIN)

AF:

0.151

AC:

8048

AN:

53280

Middle Eastern (MID)

AF:

0.177

AC:

1016

AN:

5750

European-Non Finnish (NFE)

AF:

0.107

AC:

118879

AN:

1111818

Other (OTH)

AF:

0.145

AC:

8744

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

8967

17934

26902

35869

44836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4546

9092

13638

18184

22730

<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:

0.257

AC:

38921

AN:

151718

Hom.:

9185

Cov.:

AF XY:

0.254

AC XY:

18844

AN XY:

74138

show subpopulations

African (AFR)

AF:

0.630

AC:

26116

AN:

41430

American (AMR)

AF:

0.144

AC:

2194

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.0748

AC:

259

AN:

3462

East Asian (EAS)

AF:

0.0310

AC:

159

AN:

5130

South Asian (SAS)

AF:

0.171

AC:

822

AN:

4806

European-Finnish (FIN)

AF:

0.159

AC:

1669

AN:

10516

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7100

AN:

67848

Other (OTH)

AF:

0.210

AC:

441

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

1110

2220

3331

4441

5551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.131

Hom.:

4865

Bravo

AF:

0.268

TwinsUK

AF:

0.112

AC:

414

ALSPAC

AF:

0.112

AC:

430

ESP6500AA

AF:

0.611

AC:

2684

ESP6500EA

AF:

0.104

AC:

895

ExAC

AF:

0.163

AC:

19787

Asia WGS

AF:

0.171

AC:

594

AN:

3478

EpiCase

AF:

0.106

EpiControl

AF:

0.111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.014

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0000038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

PhyloP100

0.79

PrimateAI

Benign

0.45

PROVEAN

Benign

0.92

REVEL

Benign

0.067

Sift

Benign

1.0

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.063

MPC

0.34

ClinPred

0.00069

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.059

gMVP

0.14

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over