Genetic Variant PLEKHG5:p.Arg537Pro (chr1-6470576-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020631.6(PLEKHG5):c.1610G>C(p.Arg537Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R537Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.14

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 link	c.1610G>C	p.Arg537Pro	missense_variant	Exon 15 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.1610G>C	p.Arg537Pro	missense_variant	Exon 15 of 21	2	NM_020631.6	ENSP00000366957.3		O94827-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437538

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32760

American (AMR)

AF:

0.00

AC:

AN:

42602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

37966

South Asian (SAS)

AF:

0.00

AC:

AN:

85198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106730

Other (OTH)

AF:

0.0000168

AC:

AN:

59570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

.;.;.;.;.;.;.;.;D;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.85

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

MetaSVM

Uncertain

-0.014

MutationAssessor

Uncertain

2.6

.;.;.;.;.;.;.;.;M;.

PhyloP100

4.1

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-4.0

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0080

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

Polyphen

1.0, 1.0, 0.99

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

Vest4

0.79

MutPred

0.58

.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.001);.;

MVP

0.76

MPC

0.96

ClinPred

0.99

GERP RS

3.3

Varity_R

0.88

gMVP

0.99

Mutation Taster

=57/43

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over