1-6469396-G-A

Position:

chr1-6469396-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020631.6(PLEKHG5):c.1988C>T(p.Thr663Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T663A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.07

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6 linkuse as main transcript	c.1988C>T	p.Thr663Met	missense_variant	18/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8 linkuse as main transcript	c.1988C>T	p.Thr663Met	missense_variant	18/21	2	NM_020631.6	P2	O94827-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease recessive intermediate C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 12, 2013

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 11, 2024

Variant summary: PLEKHG5 c.1988C>T (p.Thr663Met) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1988C>T has been reported in the literature in an individual affected with an intermediate form of Charcot-Marie-Tooth disease (Kim_2013). These data do not allow any conclusion about variant significance. This publication reports experimental evidence evaluating an impact on protein function, finding that the variant modestly inhibited activation of the NF-KB pathway. The following publication has been ascertained in the context of this evaluation (PMID: 23844677). ClinVar contains an entry for this variant (Variation ID: 60780). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 663 of the PLEKHG5 protein (p.Thr663Met). This variant is present in population databases (rs397515456, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 23844677). ClinVar contains an entry for this variant (Variation ID: 60780). 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"). Experimental studies have shown that this missense change affects PLEKHG5 function (PMID: 23844677). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

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

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.73

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

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

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

REVEL

Benign

0.28

Sift

Benign

0.093

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0, 0.99, 0.95

.;.;.;.;D;D;.;.;D;P

Vest4

0.79

MutPred

0.38

.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0817);.;

MVP

0.83

MPC

0.94

ClinPred

0.48

GERP RS

5.5

Varity_R

0.16

gMVP

0.61

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