Genetic Variant PLEKHG4:p.Met41Ile (chr16-67280167-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001129729.3(PLEKHG4):c.123G>A(p.Met41Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PLEKHG4
NM_001129729.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.459

Variant links:

Genes affected

PLEKHG4 (HGNC:24501): (pleckstrin homology and RhoGEF domain containing G4) The protein encoded by this gene can function as a guanine nucleotide exchange factor (GEF) and may play a role in intracellular signaling and cytoskeleton dynamics at the Golgi apparatus. Polymorphisms in the region of this gene have been found to be associated with spinocerebellar ataxia in some study populations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

PLEKHG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045220286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3 link	c.123G>A	p.Met41Ile	missense_variant	Exon 2 of 22	ENST00000379344.8	NP_001123201.1	Q58EX7-1A0A024R6X4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8 link	c.123G>A	p.Met41Ile	missense_variant	Exon 2 of 22	1	NM_001129729.3	ENSP00000368649.3		Q58EX7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251184

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.123G>A (p.M41I) alteration is located in exon 1 (coding exon 1) of the PLEKHG4 gene. This alteration results from a G to A substitution at nucleotide position 123, causing the methionine (M) at amino acid position 41 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.2

DANN

Benign

0.50

DEOGEN2

Benign

0.013

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.64

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

M_CAP

Benign

0.0054

MetaRNN

Benign

0.045

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.34

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

REVEL

Benign

0.071

Sift

Benign

0.63

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

Sift4G

Benign

0.52

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

Polyphen

0.0

B;.;.;.;.;B;B;B;.

Vest4

0.042

MutPred

0.12

Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);Loss of catalytic residue at M41 (P = 0.0258);

MVP

0.31

MPC

0.29

ClinPred

0.0081

GERP RS

-3.5

Varity_R

0.090

gMVP

0.041

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over