1-6467536-A-G

Variant names:

• chr1-6467536-A-G
• rs117494970
• NM_020631.6:c.*27T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.897
• Publications: 1 publications found

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]

PLEKHG5 Gene-Disease associations (from GenCC):

• neuromuscular disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease recessive intermediate C

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuronopathy, distal hereditary motor, autosomal recessive 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.*27T>C		3_prime_UTR_variant	Exon 21 of 21	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.*27T>C		3_prime_UTR_variant	Exon 21 of 21	2	NM_020631.6	ENSP00000366957.3

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

GnomAD2 exomes AF: 0.0110 AC: 2729 AN: 248780 AF XY: 0.0115

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 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

African (AFR) AF: 0.00141 AC: 47 AN: 33446

American (AMR) AF: 0.0175 AC: 781 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 433 AN: 26108

East Asian (EAS) AF: 0.0265 AC: 1052 AN: 39686

South Asian (SAS) AF: 0.0193 AC: 1666 AN: 86210

European-Finnish (FIN) AF: 0.0103 AC: 544 AN: 52936

Middle Eastern (MID) AF: 0.0163 AC: 94 AN: 5766

European-Non Finnish (NFE) AF: 0.00454 AC: 5045 AN: 1110550

Other (OTH) AF: 0.00719 AC: 434 AN: 60338

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

African (AFR) AF: 0.00123 AC: 51 AN: 41566

American (AMR) AF: 0.0131 AC: 201 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3468

East Asian (EAS) AF: 0.0186 AC: 96 AN: 5172

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4822

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00497 AC: 338 AN: 67988

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00654 Hom.: 7

Bravo AF: 0.00614

Asia WGS AF: 0.0220 AC: 75 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.8
DANN	Benign	0.78
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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