rs143545780

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020631.6(PLEKHG5):​c.1729G>T​(p.Ala577Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. A577T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.975
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15944293).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLEKHG5NM_020631.6 linkuse as main transcriptc.1729G>T p.Ala577Ser missense_variant 16/21 ENST00000377728.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLEKHG5ENST00000377728.8 linkuse as main transcriptc.1729G>T p.Ala577Ser missense_variant 16/212 NM_020631.6 P2O94827-5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250844
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135694
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461750
Hom.:
0
Cov.:
33
AF XY:
0.00000963
AC XY:
7
AN XY:
727180
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:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.17
.;.;.;.;.;.;.;.;T;T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.95
D;.;D;D;D;D;.;D;D;D
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.5
.;.;.;.;.;.;.;.;L;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.1
N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.036
Sift
Benign
0.13
T;T;T;T;T;D;T;T;T;D
Sift4G
Benign
0.061
T;T;T;T;T;T;T;T;T;T
Polyphen
0.59, 0.26, 0.32, 0.17
.;.;.;.;P;B;.;.;B;B
Vest4
0.41
MutPred
0.32
.;.;.;.;.;.;.;.;Gain of glycosylation at A633 (P = 0.0198);.;
MVP
0.13
MPC
0.76
ClinPred
0.80
D
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.051
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs143545780; hg19: chr1-6530367; API