rs146651455

chr1-6473355-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020631.6(PLEKHG5):c.691G>A(p.Gly231Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,551,912 control chromosomes in the GnomAD database, including 7 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: PLEKHG5 NM_020631.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.371

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028589368).
• BP6: Variant 1-6473355-C-T is Benign according to our data. Variant chr1-6473355-C-T is described in ClinVar as [Benign]. Clinvar id is 198896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00436 (665/152372) while in subpopulation AFR AF= 0.0154 (640/41582). AF 95% confidence interval is 0.0144. There are 4 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.691G>A	p.Gly231Ser	missense_variant	8/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.691G>A	p.Gly231Ser	missense_variant	8/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 663 AN: 152254 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000908 AC: 137 AN: 150854 Hom.: 1 AF XY: 0.000746 AC XY: 60 AN XY: 80416

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.000415 AC: 581 AN: 1399540 Hom.: 3 Cov.: 35 AF XY: 0.000332 AC XY: 229 AN XY: 690552

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.000807

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.000775

GnomAD4 genome AF: 0.00436 AC: 665 AN: 152372 Hom.: 4 Cov.: 34 AF XY: 0.00427 AC XY: 318 AN XY: 74506

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00506

ESP6500AA AF: 0.0111 AC: 46

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000977 AC: 102

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 31, 2014

- -

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

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.71
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.73	T;.;T;T;T;T;.;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.53	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.48	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.091	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.014, 0.021	.;.;.;.;B;B;.;.;B;B
Vest4		0.14
MVP		0.040
MPC		0.27
ClinPred		0.0031	T
GERP RS		-2.6
Varity_R		0.033
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146651455; hg19: chr1-6533415;