16-67280167-G-A

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

19

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]

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
PLEKHG4NM_001129729.3 linkc.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
PLEKHG4ENST00000379344.8 linkc.123G>A p.Met41Ile missense_variant Exon 2 of 22 1 NM_001129729.3 ENSP00000368649.3 Q58EX7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251184
Hom.:
0
AF XY:
0.0000368
AC XY:
5
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:
43
AN:
1461564
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
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.:
33
Alfa
AF:
0.0000468
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

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
T
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
N
LIST_S2
Benign
0.64
.;T;T;T;T;.;T;T;T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.045
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.81
L;.;.;.;.;L;L;L;.
PrimateAI
Benign
0.35
T
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
T
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.

Other links and lift over

dbSNP: rs369328077; hg19: chr16-67314070; API