dbSNP rs1309731055: PLEKHG5:p.Arg460Gln (chr1-6471003-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020631.6(PLEKHG5):c.1379G>A(p.Arg460Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,740 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. R460W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neuromuscular disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease recessive intermediate C
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
neuronopathy, distal hereditary motor, autosomal recessive 4
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

PLEKHG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.1379G>A	p.Arg460Gln	missense_variant	Exon 13 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.1379G>A	p.Arg460Gln	missense_variant	Exon 13 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000432

AC:

AN:

231698

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.0000227

AC:

AN:

43960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

38968

South Asian (SAS)

AF:

0.00

AC:

AN:

84794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107760

Other (OTH)

AF:

0.00

AC:

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

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

Eigen

Benign

0.026

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.48

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

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

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

PhyloP100

3.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.17

Sift

Benign

0.15

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

Sift4G

Uncertain

0.015

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

Polyphen

1.0, 1.0, 0.64

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

Vest4

0.56

MutPred

0.58

.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0481);.;

MVP

0.45

MPC

0.44

ClinPred

0.44

GERP RS

3.8

Varity_R

0.31

gMVP

0.63

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over