1-6467273-A-G

Variant names:

• chr1-6467273-A-G
• rs14708
• NM_020631.6:c.*290T>C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 2.41
• Publications: 9 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=-0.86).
• 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.
• 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 rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.*290T>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.*290T>C		3_prime_UTR_variant	Exon 21 of 21	2	NM_020631.6	ENSP00000366957.3

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

African (AFR) AF: 0.579 AC: 6864 AN: 11854

American (AMR) AF: 0.114 AC: 2202 AN: 19400

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 1773 AN: 12788

East Asian (EAS) AF: 0.00803 AC: 228 AN: 28410

South Asian (SAS) AF: 0.154 AC: 7151 AN: 46516

European-Finnish (FIN) AF: 0.165 AC: 4341 AN: 26380

Middle Eastern (MID) AF: 0.196 AC: 351 AN: 1788

European-Non Finnish (NFE) AF: 0.141 AC: 34528 AN: 244048

Other (OTH) AF: 0.168 AC: 4030 AN: 23948

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

African (AFR) AF: 0.580 AC: 24073 AN: 41498

American (AMR) AF: 0.159 AC: 2426 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3468

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5172

South Asian (SAS) AF: 0.161 AC: 775 AN: 4826

European-Finnish (FIN) AF: 0.158 AC: 1671 AN: 10608

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9701 AN: 68008

Other (OTH) AF: 0.224 AC: 474 AN: 2116

Alfa AF: 0.181 Hom.: 4411

Bravo AF: 0.274

Asia WGS AF: 0.129 AC: 448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.59
PhyloP100		2.4
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: rs14708; hg19: chr1-6527333;