1-6467273-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020631.6(PLEKHG5):c.*290T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 567,324 control chromosomes in the GnomAD database, including 14,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (8198 hom., cov: 33)
  • Exomes 𝑓: 0.15 (6303 hom.)
• Consequence: PLEKHG5 NM_020631.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.41

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 (BayesDel_noAF=-0.86).
• BP6: Variant 1-6467273-A-G is Benign according to our data. Variant chr1-6467273-A-G is described in ClinVar as [Benign]. Clinvar id is 297928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6467273-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.*290T>C		3_prime_UTR_variant	21/21	ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.*290T>C		3_prime_UTR_variant	21/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39741 AN: 152074 Hom.: 8164 Cov.: 33

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.148 AC: 61468 AN: 415132 Hom.: 6303 Cov.: 0 AF XY: 0.146 AC XY: 31954 AN XY: 218202

Gnomad4 AFR exome AF: 0.579

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.00803

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.262 AC: 39828 AN: 152192 Hom.: 8198 Cov.: 33 AF XY: 0.259 AC XY: 19294 AN XY: 74396

Gnomad4 AFR AF: 0.580

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.224

Alfa AF: 0.166 Hom.: 2675

Bravo AF: 0.274

Asia WGS AF: 0.129 AC: 448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	12
Dann	Benign	0.59

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: rs14708; hg19: chr1-6527333;