rs183712624

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020631.6(PLEKHG5):c.571C>T(p.Arg191Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,346,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 2.14

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23387039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 linkuse as main transcript	c.571C>T	p.Arg191Trp	missense_variant	7/21	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.571C>T	p.Arg191Trp	missense_variant	7/21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

AF:

0.0000809

AC:

AN:

135942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000737

Gnomad ASJ

AF:

0.000306

Gnomad EAS

AF:

0.000806

Gnomad SAS

AF:

0.000549

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000631

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000424

AC:

AN:

235596

Hom.:

AF XY:

0.0000310

AC XY:

AN XY:

128964

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000892

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.0000679

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1210816

Hom.:

Cov.:

AF XY:

0.0000467

AC XY:

AN XY:

599470

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.0000813

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000742

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000358

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000809

AC:

AN:

136050

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

65594

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000736

Gnomad4 ASJ

AF:

0.000306

Gnomad4 EAS

AF:

0.000806

Gnomad4 SAS

AF:

0.000547

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000631

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 09-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the PLEKHG5 protein (p.Arg191Trp). This variant is present in population databases (rs183712624, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 297969). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neuronopathy, distal hereditary motor, autosomal recessive 4

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2024

The c.571C>T (p.R191W) alteration is located in exon 7 (coding exon 6) of the PLEKHG5 gene. This alteration results from a C to T substitution at nucleotide position 571, causing the arginine (R) at amino acid position 191 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

.;.;.;.;.;.;.;.;D;T

Eigen

Benign

-0.013

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.23

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

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.1

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

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.0

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

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.32

MVP

0.63

MPC

0.27

ClinPred

0.42

GERP RS

0.78

Varity_R

0.23

gMVP

0.62

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