rs148560273

Positions:

chr1-6468255-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020631.6(PLEKHG5):c.2581C>T(p.Arg861Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,603,370 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 3 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.837

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=0.0058948696).

BP6

Variant 1-6468255-G-A is Benign according to our data. Variant chr1-6468255-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 384612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00403 (614/152320) while in subpopulation AFR AF= 0.0142 (590/41572). AF 95% confidence interval is 0.0132. There are 4 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 linkuse as main transcript	c.2581C>T	p.Arg861Cys	missense_variant	20/21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8 linkuse as main transcript	c.2581C>T	p.Arg861Cys	missense_variant	20/21	2	NM_020631.6	ENSP00000366957	P2	O94827-5

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

612

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000994

AC:

238

AN:

239478

Hom.:

AF XY:

0.000665

AC XY:

AN XY:

130790

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.000704

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000338

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000653

Gnomad OTH exome

AF:

0.000511

GnomAD4 exome

AF:

0.000356

AC:

517

AN:

1451050

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

212

AN XY:

719954

show subpopulations

Gnomad4 AFR exome

AF:

0.0114

Gnomad4 AMR exome

AF:

0.000856

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000702

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000416

Gnomad4 OTH exome

AF:

0.000768

GnomAD4 genome

AF:

0.00403

AC:

614

AN:

152320

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0142

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00222

Hom.:

Bravo

AF:

0.00459

ESP6500AA

AF:

0.0117

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00118

AC:

143

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2016

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. -

Neuronopathy, distal hereditary motor, autosomal recessive 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

PLEKHG5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 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

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

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

MetaRNN

Benign

0.0059

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

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.2

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

REVEL

Benign

0.21

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.011

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

Polyphen

1.0, 1.0, 0.99

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

Vest4

0.20

MVP

0.65

MPC

1.1

ClinPred

0.044

GERP RS

3.9

Varity_R

0.17

gMVP

0.51

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