Genetic Variant NM_001129729.3:c.1574A>G (chr16-67284339-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 0.26 ( 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

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=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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3 link	c.1574A>G	p.Asp525Gly	missense_variant	Exon 12 of 22	ENST00000379344.8	NP_001123201.1	Q58EX7-1A0A024R6X4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8 link	c.1574A>G	p.Asp525Gly	missense_variant	Exon 12 of 22	1	NM_001129729.3	ENSP00000368649.3		Q58EX7-1

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

GnomAD3 exomes

AF:

0.149

AC:

37172

AN:

248826

Hom.:

5007

AF XY:

0.144

AC XY:

19407

AN XY:

134978

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 SAS exome

AF:

0.182

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

Gnomad4 AFR exome

AF:

0.654

Gnomad4 AMR exome

AF:

0.114

Gnomad4 ASJ exome

AF:

0.0881

Gnomad4 EAS exome

AF:

0.0220

Gnomad4 SAS exome

AF:

0.173

Gnomad4 FIN exome

AF:

0.151

Gnomad4 NFE exome

AF:

0.107

Gnomad4 OTH exome

AF:

0.145

GnomAD4 genome

AF:

0.257

AC:

38921

AN:

151718

Hom.:

9185

Cov.:

AF XY:

0.254

AC XY:

18844

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.630

Gnomad4 AMR

AF:

0.144

Gnomad4 ASJ

AF:

0.0748

Gnomad4 EAS

AF:

0.0310

Gnomad4 SAS

AF:

0.171

Gnomad4 FIN

AF:

0.159

Gnomad4 NFE

AF:

0.105

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.123

Hom.:

3334

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.13

DEOGEN2

Benign

0.014

T;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.33

.;.;T;T

MetaRNN

Benign

0.0000038

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

N;N;N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

0.92

N;N;N;N

REVEL

Benign

0.067

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.83

T;T;T;T

Polyphen

0.0

B;B;B;B

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

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