dbSNP rs740842: PLEKHG6:p.Ala35Thr (chr12-6312329-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001384598.1(PLEKHG6):c.103G>A(p.Ala35Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,580,040 control chromosomes in the GnomAD database, including 253,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.56 ( 24423 hom., cov: 32)

Exomes 𝑓: 0.56 ( 229412 hom. )

Consequence

PLEKHG6
NM_001384598.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.297

Variant links:

Genes affected

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.6391135E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG6	NM_001384598.1 link	c.103G>A	p.Ala35Thr	missense_variant	Exon 2 of 16	ENST00000684764.1	NP_001371527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG6	ENST00000684764.1 link	c.103G>A	p.Ala35Thr	missense_variant	Exon 2 of 16		NM_001384598.1	ENSP00000506982.1		Q3KR16-1

Frequencies

GnomAD3 genomes

AF:

0.561

AC:

85330

AN:

151968

Hom.:

24393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.602

Gnomad AMI

AF:

0.549

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.516

Gnomad EAS

AF:

0.259

Gnomad SAS

AF:

0.416

Gnomad FIN

AF:

0.605

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.591

Gnomad OTH

AF:

0.513

GnomAD3 exomes

AF:

0.513

AC:

112819

AN:

219970

Hom.:

30317

AF XY:

0.514

AC XY:

61759

AN XY:

120226

show subpopulations

Gnomad AFR exome

AF:

0.594

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.498

Gnomad EAS exome

AF:

0.242

Gnomad SAS exome

AF:

0.421

Gnomad FIN exome

AF:

0.597

Gnomad NFE exome

AF:

0.580

Gnomad OTH exome

AF:

0.524

GnomAD4 exome

AF:

0.562

AC:

802323

AN:

1427954

Hom.:

229412

Cov.:

AF XY:

0.559

AC XY:

396896

AN XY:

710088

show subpopulations

Gnomad4 AFR exome

AF:

0.597

Gnomad4 AMR exome

AF:

0.402

Gnomad4 ASJ exome

AF:

0.495

Gnomad4 EAS exome

AF:

0.268

Gnomad4 SAS exome

AF:

0.433

Gnomad4 FIN exome

AF:

0.597

Gnomad4 NFE exome

AF:

0.587

Gnomad4 OTH exome

AF:

0.540

GnomAD4 genome

AF:

0.562

AC:

85401

AN:

152086

Hom.:

24423

Cov.:

AF XY:

0.557

AC XY:

41431

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.602

Gnomad4 AMR

AF:

0.457

Gnomad4 ASJ

AF:

0.516

Gnomad4 EAS

AF:

0.259

Gnomad4 SAS

AF:

0.417

Gnomad4 FIN

AF:

0.605

Gnomad4 NFE

AF:

0.591

Gnomad4 OTH

AF:

0.515

Alfa

AF:

0.569

Hom.:

52502

Bravo

AF:

0.549

TwinsUK

AF:

0.582

AC:

2157

ALSPAC

AF:

0.593

AC:

2285

ESP6500AA

AF:

0.601

AC:

2646

ESP6500EA

AF:

0.573

AC:

4925

ExAC

AF:

0.518

AC:

62935

Asia WGS

AF:

0.349

AC:

1215

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.0

DANN

Benign

0.95

DEOGEN2

Benign

0.016

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.53

.;T;T

MetaRNN

Benign

0.000026

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.0

M;.;M

PrimateAI

Benign

0.31

PROVEAN

Benign

0.16

N;N;N

REVEL

Benign

0.024

Sift

Uncertain

0.026

D;T;D

Sift4G

Benign

0.065

T;T;T

Polyphen

0.099

B;B;B

Vest4

0.025

MPC

0.13

ClinPred

0.010

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.038

gMVP

0.44

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over