Genetic Variant PLEKHG5:p.Val103Met (chr1-6474583-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020631.6(PLEKHG5):c.307G>A(p.Val103Met) variant causes a missense change. The variant allele was found at a frequency of 0.00305 in 1,613,564 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V103L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 8 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.54

Publications

9 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, autosomal recessive 4
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

PLEKHG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010727793).

BP6

Variant 1-6474583-C-T is Benign according to our data. Variant chr1-6474583-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245660.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00211 (322/152314) while in subpopulation NFE AF = 0.00329 (224/68012). AF 95% confidence interval is 0.00294. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020631.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG5	NM_020631.6	MANE Select	c.307G>A	p.Val103Met	missense	Exon 6 of 21	NP_065682.2
PLEKHG5	NM_001265593.2		c.514G>A	p.Val172Met	missense	Exon 6 of 21	NP_001252522.1	A0A804EMX3
PLEKHG5	NM_001042663.3		c.418G>A	p.Val140Met	missense	Exon 7 of 22	NP_001036128.2	O94827-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.307G>A	p.Val103Met	missense	Exon 6 of 21	ENSP00000366957.3	O94827-5
PLEKHG5	ENST00000377732.5	TSL:1	c.418G>A	p.Val140Met	missense	Exon 6 of 21	ENSP00000366961.1	O94827-3
PLEKHG5	ENST00000400915.8	TSL:1	c.418G>A	p.Val140Met	missense	Exon 7 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

322

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00190

AC:

475

AN:

250140

AF XY:

0.00191

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.000697

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00327

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00315

AC:

4604

AN:

1461250

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

2240

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.00143

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000842

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000730

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

52850

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00385

AC:

4284

AN:

1111962

Other (OTH)

AF:

0.00224

AC:

135

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

240

479

719

958

1198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00211

AC:

322

AN:

152314

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41558

American (AMR)

AF:

0.00281

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00329

AC:

224

AN:

68012

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00326

Hom.:

Bravo

AF:

0.00229

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00194

AC:

236

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00284

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Neuronopathy, distal hereditary motor, autosomal recessive 4 (1)

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (1)

not specified (1)

PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.0098

MutationAssessor

Benign

1.9

PhyloP100

4.5

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.43

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.66

MVP

0.80

MPC

0.92

ClinPred

0.029

GERP RS

4.5

Varity_R

0.28

gMVP

0.54

Mutation Taster

=67/33

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over