rs61730399

chr1-6473042-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 3.47

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 -9 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: {Uncertain_significance=3, Likely_benign=5}. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.928G>A	p.Asp310Asn	missense_variant	9/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.928G>A	p.Asp310Asn	missense_variant	9/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152214 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.00243 AC XY: 329 AN XY: 135416

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.: 12 Cov.: 34 AF XY: 0.00272 AC XY: 1976 AN XY: 727144

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.: 0 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74484

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.: 5

Bravo AF: 0.00237

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00260 AC: 316

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	- -
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. -

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

Invitae

Jan 31, 2024

- -

PLEKHG5-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs61730399; hg19: chr1-6533102; COSMIC: COSV104652048; COSMIC: COSV104652048;