1-6467536-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020631.6(PLEKHG5):c.*27T>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 0.00687 in 1,612,012 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (95 hom.)
• Consequence: PLEKHG5 NM_020631.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.897

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-6467536-A-G is Benign according to our data. Variant chr1-6467536-A-G is described in ClinVar as [Benign]. Clinvar id is 297932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00642 (978/152252) while in subpopulation EAS AF= 0.0186 (96/5172). AF 95% confidence interval is 0.0156. There are 12 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.*27T>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.*27T>C		3_prime_UTR_variant	21/21	2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 979 AN: 152134 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0110 AC: 2729 AN: 248780 Hom.: 39 AF XY: 0.0115 AC XY: 1544 AN XY: 134690

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.0161

Gnomad SAS exome AF: 0.0204

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00655

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00692 AC: 10096 AN: 1459760 Hom.: 95 Cov.: 30 AF XY: 0.00746 AC XY: 5420 AN XY: 726364

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0265

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.00454

Gnomad4 OTH exome AF: 0.00719

GnomAD4 genome AF: 0.00642 AC: 978 AN: 152252 Hom.: 12 Cov.: 33 AF XY: 0.00697 AC XY: 519 AN XY: 74444

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0186

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00678 Hom.: 1

Bravo AF: 0.00614

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.8
Dann	Benign	0.78

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: rs117494970; hg19: chr1-6527596; COSMIC: COSV61068635; COSMIC: COSV61068635;