Genetic Variant PLEKHG5:p.Pro12Thr (chr1-6477538-G-T) – ACMG Classification: Benign (-20 pts)

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.34C>A(p.Pro12Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000681 in 1,611,942 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 15 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.90

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009963274).

BP6

Variant 1-6477538-G-T is Benign according to our data. Variant chr1-6477538-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 246031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000381 (58/152360) while in subpopulation SAS AF = 0.00435 (21/4830). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 15 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.34C>A	p.Pro12Thr	missense	Exon 2 of 21	NP_065682.2
PLEKHG5	NM_001265593.2		c.241C>A	p.Pro81Thr	missense	Exon 2 of 21	NP_001252522.1	A0A804EMX3
PLEKHG5	NM_001042663.3		c.145C>A	p.Pro49Thr	missense	Exon 3 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.34C>A	p.Pro12Thr	missense	Exon 2 of 21	ENSP00000366957.3	O94827-5
PLEKHG5	ENST00000377732.5	TSL:1	c.145C>A	p.Pro49Thr	missense	Exon 2 of 21	ENSP00000366961.1	O94827-3
PLEKHG5	ENST00000400915.8	TSL:1	c.145C>A	p.Pro49Thr	missense	Exon 3 of 22	ENSP00000383706.4	O94827-3

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00141

AC:

352

AN:

249314

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000504

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000712

AC:

1039

AN:

1459582

Hom.:

Cov.:

AF XY:

0.000957

AC XY:

695

AN XY:

726222

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.000514

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00851

AC:

734

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51230

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000174

AC:

193

AN:

1111926

Other (OTH)

AF:

0.00109

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000381

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41580

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68038

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000322

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronopathy, distal hereditary motor, autosomal recessive 4 (2)

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C (2)

not provided (2)

Charcot-Marie-Tooth disease recessive intermediate C (1)

Inborn genetic diseases (1)

PLEKHG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.5

PhyloP100

3.9

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.14

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.037

Polyphen

0.91

Vest4

0.54

MVP

0.78

MPC

0.98

ClinPred

0.050

GERP RS

3.6

PromoterAI

-0.054

Neutral

(source)

Varity_R

0.15

gMVP

0.22

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over