rs111400494

chr1-6475992-G-Achr1-6475992-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020631.6(PLEKHG5):c.88C>T(p.Arg30Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00461 in 1,613,838 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (26 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 4.65

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009325266).
• BP6: Variant 1-6475992-G-A is Benign according to our data. Variant chr1-6475992-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245659.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00268 (409/152364) while in subpopulation NFE AF= 0.00457 (311/68030). AF 95% confidence interval is 0.00415. There are 1 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.88C>T	p.Arg30Cys	missense_variant	3/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.88C>T	p.Arg30Cys	missense_variant	3/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152246 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00240 AC: 601 AN: 250318 Hom.: 2 AF XY: 0.00241 AC XY: 327 AN XY: 135534

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00481 AC: 7035 AN: 1461474 Hom.: 26 Cov.: 33 AF XY: 0.00474 AC XY: 3445 AN XY: 727064

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.000981

Gnomad4 NFE exome AF: 0.00577

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00268 AC: 409 AN: 152364 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74508

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00457

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00378 Hom.: 1

Bravo AF: 0.00255

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00225 AC: 273

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PLEKHG5: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The PLEKHG5 c.88C>T; p.Arg30Cys variant (rs111400494), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 245659). This variant is found in the non-Finnish European population with an allele frequency of 0.4% (503/128,500 alleles, including 2 homozygotes) in the Genome Aggregation Database. The arginine at codon 30 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.225). Due to limited information, the clinical significance of the p.Arg30Cys variant is uncertain at this time. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -

Neuronopathy, distal hereditary motor, autosomal recessive 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PLEKHG5-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0093	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.028	D;D;D;D;D;D;D;D;D;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D
Polyphen		0.49, 0.27, 0.18, 0.20	.;.;.;.;P;B;.;.;B;B
Vest4		0.48
MVP		0.56
MPC		0.35
ClinPred		0.019	T
GERP RS		3.5
Varity_R		0.22
gMVP		0.35

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: rs111400494; hg19: chr1-6536052;