rs111400494

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020631.6(PLEKHG5):c.88C>T(p.Arg30Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00461 in 1,613,838 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 26 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 4.65

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:

PLEKHG5 (HGNC:):

PLEKHG5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009325266).

BP6

Variant 1-6475992-G-A is Benign according to our data. Variant chr1-6475992-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245659.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00268 (409/152364) while in subpopulation NFE AF= 0.00457 (311/68030). AF 95% confidence interval is 0.00415. There are 1 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 linkuse as main transcript	c.88C>T	p.Arg30Cys	missense_variant	3/21	ENST00000377728.8	NP_065682.2	O94827-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8 linkuse as main transcript	c.88C>T	p.Arg30Cys	missense_variant	3/21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

410

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00457

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00240

AC:

601

AN:

250318

Hom.:

AF XY:

0.00241

AC XY:

327

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00707

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.000752

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00481

AC:

7035

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3445

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00727

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000974

Gnomad4 FIN exome

AF:

0.000981

Gnomad4 NFE exome

AF:

0.00577

Gnomad4 OTH exome

AF:

0.00381

GnomAD4 genome

AF:

0.00268

AC:

409

AN:

152364

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00457

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00378

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00225

AC:

273

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PLEKHG5: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The PLEKHG5 c.88C>T; p.Arg30Cys variant (rs111400494), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 245659). This variant is found in the non-Finnish European population with an allele frequency of 0.4% (503/128,500 alleles, including 2 homozygotes) in the Genome Aggregation Database. The arginine at codon 30 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.225). Due to limited information, the clinical significance of the p.Arg30Cys variant is uncertain at this time. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -

Neuronopathy, distal hereditary motor, autosomal recessive 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

PLEKHG5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

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

Eigen

Benign

-0.084

Eigen_PC

Benign

-0.024

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.95

D;.;D;D;D;D;.;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0093

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

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.9

.;.;.;.;.;.;.;.;L;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.028

D;D;D;D;D;D;D;D;D;T

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D

Polyphen

0.49, 0.27, 0.18, 0.20

.;.;.;.;P;B;.;.;B;B

Vest4

0.48

MVP

0.56

MPC

0.35

ClinPred

0.019

GERP RS

3.5

Varity_R

0.22

gMVP

0.35

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