Variant rs11860295 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3 link	c.1235C>T	p.Thr412Ile	missense_variant	9/22	ENST00000379344.8	NP_001123201.1	Q58EX7-1A0A024R6X4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8 link	c.1235C>T	p.Thr412Ile	missense_variant	9/22	1	NM_001129729.3	ENSP00000368649.3		Q58EX7-1

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

GnomAD3 exomes

AF:

0.118

AC:

29259

AN:

247982

Hom.:

3773

AF XY:

0.113

AC XY:

15221

AN XY:

134436

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 SAS exome

AF:

0.152

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

Gnomad4 AFR exome

AF:

0.594

Gnomad4 AMR exome

AF:

0.0696

Gnomad4 ASJ exome

AF:

0.0703

Gnomad4 EAS exome

AF:

0.00272

Gnomad4 SAS exome

AF:

0.144

Gnomad4 FIN exome

AF:

0.140

Gnomad4 NFE exome

AF:

0.0741

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.219

AC:

33320

AN:

152102

Hom.:

7367

Cov.:

AF XY:

0.217

AC XY:

16161

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.571

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.0605

Gnomad4 EAS

AF:

0.00485

Gnomad4 SAS

AF:

0.138

Gnomad4 FIN

AF:

0.148

Gnomad4 NFE

AF:

0.0740

Gnomad4 OTH

AF:

0.167

Alfa

AF:

0.106

Hom.:

3243

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

T;T;T;.

Eigen

Benign

-0.079

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.58

.;.;T;T

MetaRNN

Benign

0.000043

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Benign

0.061

Sift

Benign

0.27

T;T;T;T

Sift4G

Benign

0.078

T;T;T;T

Polyphen

0.27

B;B;B;D

Vest4

0.057

MPC

0.29

ClinPred

0.017

GERP RS

3.2

Varity_R

0.036

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over