chr1-6473042-C-T

Position:

chr1-6473042-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020631.6(PLEKHG5):c.928G>A(p.Asp310Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,614,058 control chromosomes in the GnomAD database, including 12 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 12 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 3.47

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]

PLEKHG5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036782324).

BP6

Variant 1-6473042-C-T is Benign according to our data. Variant chr1-6473042-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297961.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr1-6473042-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00236 (359/152332) while in subpopulation AMR AF= 0.00536 (82/15312). AF 95% confidence interval is 0.00442. There are 0 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG5	NM_020631.6 linkuse as main transcript	c.928G>A	p.Asp310Asn	missense_variant	9/21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8 linkuse as main transcript	c.928G>A	p.Asp310Asn	missense_variant	9/21	2	NM_020631.6	ENSP00000366957	P2	O94827-5

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

358

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00536

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00257

AC:

644

AN:

250440

Hom.:

AF XY:

0.00243

AC XY:

329

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00618

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00288

AC:

4207

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1976

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.00658

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00274

Gnomad4 NFE exome

AF:

0.00320

Gnomad4 OTH exome

AF:

0.00268

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152332

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00285

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.00237

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00260

AC:

316

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	The PLEKHG5 c.928G>A; p.Asp310Asn variant (rs61730399), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 297961). This variant is found in the general population with an overall allele frequency of 0.25% (702/281,830 alleles, including 1 homozygote) in the Genome Aggregation Database. The aspartic acid at codon 310 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.075). However, due to limited information, the clinical significance of the p.Asp310Asn variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 15, 2024

Variant summary: PLEKHG5 c.928G>A (p.Asp310Asn) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 250440 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PLEKHG5 causing Distal Spinal Muscular Atrophy, Autosomal Recessive 4 phenotype (0.0011), strongly suggesting that the variant is benign. c.928G>A has been reported in the literature in an individual affected with Charcot-Marie-Tooth disease without evidence of causality (Cortese_2020). This report does not provide unequivocal conclusions about association of the variant with Distal Spinal Muscular Atrophy, Autosomal Recessive 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31827005). ClinVar contains an entry for this variant (Variation ID: 297961). Based on the evidence outlined above, the variant was classified as likely benign. -

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 11, 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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

PLEKHG5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

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

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.064

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.88

D;.;D;D;D;D;.;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0037

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

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

0.93

D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.075

Sift

Uncertain

0.023

D;T;T;D;D;D;T;D;D;D

Sift4G

Uncertain

0.040

D;D;D;D;D;D;D;D;D;T

Polyphen

0.73, 0.61, 0.033

.;.;.;.;P;P;.;.;P;B

Vest4

0.43

MVP

0.59

MPC

0.72

ClinPred

0.029

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.066

gMVP

0.25

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