1-6474063-C-T

Position:

• chr1-6474063-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_020631.6(PLEKHG5):​c.541G>A​(p.Ala181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000975 in 1,610,212 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.301

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0059225857).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000118 (18/151908) while in subpopulation SAS AF= 0.00146 (7/4800). AF 95% confidence interval is 0.000684. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.541G>A	p.Ala181Thr	missense_variant	7/21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.541G>A	p.Ala181Thr	missense_variant	7/21	2	NM_020631.6	ENSP00000366957	P2

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151790 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000205 AC: 50 AN: 243374 Hom.: 0 AF XY: 0.000226 AC XY: 30 AN XY: 132816

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.0000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.000760

Gnomad FIN exome AF: 0.000477

Gnomad NFE exome AF: 0.0000642

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000953 AC: 139 AN: 1458304 Hom.: 0 Cov.: 38 AF XY: 0.000119 AC XY: 86 AN XY: 725366

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.000895

Gnomad4 FIN exome AF: 0.000345

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151908 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74294

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000672 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21902652) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2017	- -

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 181 of the PLEKHG5 protein (p.Ala181Thr). This variant is present in population databases (rs527341275, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 245720). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;.;.;.;.;.;.;.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.69	T;.;T;T;T;T;.;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0059	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	.;.;.;.;.;.;.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.039	D;D;D;D;D;D;D;D;D;D
Polyphen		0.046, 0.0050, 0.011, 0.027	.;.;.;.;B;B;.;.;B;B
Vest4		0.059
MVP		0.16
MPC		0.25
ClinPred		0.015	T
GERP RS		-0.64
Varity_R		0.038
gMVP		0.20

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

Other links and lift over

dbSNP: rs527341275; hg19: chr1-6534123;