1-6474583-C-T

Variant names:

• chr1-6474583-C-T
• rs141032388
• NM_020631.6:c.307G>A

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.307G>A​(p.Val103Met) variant causes a missense change. The variant allele was found at a frequency of 0.00305 in 1,613,564 control chromosomes in the GnomAD database, including 8 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. V103L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 4.54

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=0.010727793).
• BP6: Variant 1-6474583-C-T is Benign according to our data. Variant chr1-6474583-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245660.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00211 (322/152314) while in subpopulation NFE AF= 0.00329 (224/68012). AF 95% confidence interval is 0.00294. There are 0 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.307G>A	p.Val103Met	missense_variant	Exon 6 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.307G>A	p.Val103Met	missense_variant	Exon 6 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00190 AC: 475 AN: 250140 Hom.: 0 AF XY: 0.00191 AC XY: 259 AN XY: 135652

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00315 AC: 4604 AN: 1461250 Hom.: 8 Cov.: 34 AF XY: 0.00308 AC XY: 2240 AN XY: 726956

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.000284

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00201 AC XY: 150 AN XY: 74478

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00229

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLEKHG5 c.307G>A; p.Val103Met variant (rs141032388), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 245660). This variant is found in the general population with an allele frequency of 0.19% (531/281480 alleles) in the Genome Aggregation Database. The valine at codon 103 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.426). Due to limited information, the clinical significance of this variant is uncertain at this time. -

not specified Benign:1

Feb 03, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PLEKHG5 c.307G>A (p.Val103Met) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 250140 control chromosomes. The observed variant frequency is approximately 2 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). To our knowledge, no occurrence of c.307G>A in individuals affected with Distal Spinal Muscular Atrophy, Autosomal Recessive 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 245660). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 18, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PLEKHG5-related disorder Benign:1

Feb 03, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	Uncertain	0.47
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;.;.;.;.;.;.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.0098	D
MutationAssessor	Benign	1.9	.;.;.;.;.;.;.;.;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;D;.;.;D;D
Vest4		0.66
MVP		0.80
MPC		0.92
ClinPred		0.029	T
GERP RS		4.5
Varity_R		0.28
gMVP		0.54

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: rs141032388; hg19: chr1-6534643;