1-6473333-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020631.6(PLEKHG5):c.713C>G(p.Thr238Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,558,310 control chromosomes in the GnomAD database, including 30,376 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 9579 hom., cov: 34)

Exomes 𝑓: 0.15 ( 20797 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.854

Variant links:

Genes affected

PLEKHG5 (HGNC:29105): (pleckstrin homology and RhoGEF domain containing G5) This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

PLEKHG5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.980708E-6).

BP6

Variant 1-6473333-G-C is Benign according to our data. Variant chr1-6473333-G-C is described in ClinVar as [Benign]. Clinvar id is 198895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6473333-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.713C>G	p.Thr238Ser	missense_variant	Exon 8 of 21	ENST00000377728.8	NP_065682.2	O94827-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8 link	c.713C>G	p.Thr238Ser	missense_variant	Exon 8 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

42074

AN:

152180

Hom.:

9529

Cov.:

show subpopulations

Gnomad AFR

AF:

0.631

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.00730

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.236

GnomAD3 exomes

AF:

0.158

AC:

25070

AN:

158834

Hom.:

3214

AF XY:

0.153

AC XY:

12987

AN XY:

85124

show subpopulations

Gnomad AFR exome

AF:

0.645

Gnomad AMR exome

AF:

0.0990

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.00716

Gnomad SAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.149

AC:

209913

AN:

1406012

Hom.:

20797

Cov.:

AF XY:

0.149

AC XY:

103376

AN XY:

694512

show subpopulations

Gnomad4 AFR exome

AF:

0.656

Gnomad4 AMR exome

AF:

0.108

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.00908

Gnomad4 SAS exome

AF:

0.163

Gnomad4 FIN exome

AF:

0.165

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.170

GnomAD4 genome

AF:

0.277

AC:

42183

AN:

152298

Hom.:

9579

Cov.:

AF XY:

0.274

AC XY:

20383

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.632

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.136

Gnomad4 EAS

AF:

0.00732

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.143

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.179

Hom.:

1184

Bravo

AF:

0.291

TwinsUK

AF:

0.131

AC:

487

ALSPAC

AF:

0.132

AC:

508

ESP6500AA

AF:

0.557

AC:

2342

ESP6500EA

AF:

0.128

AC:

1057

ExAC

AF:

0.128

AC:

13680

Asia WGS

AF:

0.143

AC:

495

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 31, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal recessive 4

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Charcot-Marie-Tooth disease recessive intermediate C

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.3

DANN

Benign

0.12

DEOGEN2

Benign

0.049

.;.;.;.;.;.;.;.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00094

LIST_S2

Benign

0.19

T;.;T;T;T;T;.;T;T;T

MetaRNN

Benign

0.0000070

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

0.81

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.97

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.95

T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;.;.;B;B;.;.;B;B

Vest4

0.042

MutPred

0.15

.;.;.;.;.;.;.;.;Gain of glycosylation at T294 (P = 0.043);.;

MPC

0.23

ClinPred

0.0011

GERP RS

0.98

Varity_R

0.034

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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