rs117505788

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020631.6(PLEKHG5):c.260T>C(p.Ile87Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00142 in 1,612,190 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I87F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 31 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.86

Publications

6 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026628375).

BP6

Variant 1-6475089-A-G is Benign according to our data. Variant chr1-6475089-A-G is described in ClinVar as Benign. ClinVar VariationId is 297975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00181 (276/152184) while in subpopulation EAS AF = 0.0442 (228/5160). AF 95% confidence interval is 0.0395. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.260T>C	p.Ile87Thr	missense_variant	Exon 5 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8 link	c.260T>C	p.Ile87Thr	missense_variant	Exon 5 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.0441

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00384

AC:

965

AN:

251482

AF XY:

0.00366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.0468

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00138

AC:

2015

AN:

1460006

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

997

AN XY:

726476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00567

AC:

148

AN:

26120

East Asian (EAS)

AF:

0.0412

AC:

1635

AN:

39686

South Asian (SAS)

AF:

0.000905

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1110346

Other (OTH)

AF:

0.00179

AC:

108

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152184

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41522

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.0442

AC:

228

AN:

5160

South Asian (SAS)

AF:

0.00229

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00256

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00360

AC:

437

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 02, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Feb 22, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

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

MetaRNN

Benign

0.0027

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

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

PhyloP100

3.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.95

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

REVEL

Benign

0.20

Sift

Benign

0.037

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

Sift4G

Uncertain

0.0060

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

Vest4

0.56

ClinPred

0.044

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.19

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over