1-6474033-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_020631.6(PLEKHG5):c.571C>T(p.Arg191Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,346,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R191Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 2.14

Publications

3 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23387039).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000438 (53/1210816) while in subpopulation EAS AF = 0.000742 (13/17526). AF 95% confidence interval is 0.000439. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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
PLEKHG5	NM_020631.6	MANE Select	c.571C>T	p.Arg191Trp	missense	Exon 7 of 21	NP_065682.2
PLEKHG5	NM_001265593.2		c.778C>T	p.Arg260Trp	missense	Exon 7 of 21	NP_001252522.1
PLEKHG5	NM_001042663.3		c.682C>T	p.Arg228Trp	missense	Exon 8 of 22	NP_001036128.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG5	ENST00000377728.8	TSL:2 MANE Select	c.571C>T	p.Arg191Trp	missense	Exon 7 of 21	ENSP00000366957.3
PLEKHG5	ENST00000377732.5	TSL:1	c.682C>T	p.Arg228Trp	missense	Exon 7 of 21	ENSP00000366961.1
PLEKHG5	ENST00000400915.8	TSL:1	c.682C>T	p.Arg228Trp	missense	Exon 8 of 22	ENSP00000383706.4

Frequencies

GnomAD3 genomes

AF:

0.0000809

AC:

AN:

135942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000737

Gnomad ASJ

AF:

0.000306

Gnomad EAS

AF:

0.000806

Gnomad SAS

AF:

0.000549

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000631

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000424

AC:

AN:

235596

AF XY:

0.0000310

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000892

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1210816

Hom.:

Cov.:

AF XY:

0.0000467

AC XY:

AN XY:

599470

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26318

American (AMR)

AF:

0.0000813

AC:

AN:

36920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16994

East Asian (EAS)

AF:

0.000742

AC:

AN:

17526

South Asian (SAS)

AF:

0.0000243

AC:

AN:

82150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3840

European-Non Finnish (NFE)

AF:

0.0000358

AC:

AN:

950946

Other (OTH)

AF:

0.00

AC:

AN:

43920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000809

AC:

AN:

136050

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

65594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37368

American (AMR)

AF:

0.0000736

AC:

AN:

13592

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

3272

East Asian (EAS)

AF:

0.000806

AC:

AN:

3720

South Asian (SAS)

AF:

0.000547

AC:

AN:

3654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000631

AC:

AN:

63368

Other (OTH)

AF:

0.00

AC:

AN:

1920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.000194

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000414

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.013

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.1

PhyloP100

2.1

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.32

MVP

0.63

MPC

0.27

ClinPred

0.42

GERP RS

0.78

Varity_R

0.23

gMVP

0.62

Mutation Taster

=70/30

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over