1-6467685-C-T

Variant names:

• chr1-6467685-C-T
• rs9435269
• NM_020631.6:c.3012-113G>A

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.3012-113G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,451,546 control chromosomes in the GnomAD database, including 13,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (6136 hom., cov: 33)
  • Exomes 𝑓: 0.076 (7634 hom.)
• Consequence: PLEKHG5 NM_020631.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.10
• Publications: 4 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=-0.89).
• BP6: Variant 1-6467685-C-T is Benign according to our data. Variant chr1-6467685-C-T is described in ClinVar as [Benign]. Clinvar id is 667940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.3012-113G>A		intron_variant	Intron 20 of 20	ENST00000377728.8	NP_065682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.3012-113G>A		intron_variant	Intron 20 of 20	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29469 AN: 152116 Hom.: 6102 Cov.: 33

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0915

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.0762 AC: 99030 AN: 1299312 Hom.: 7634 Cov.: 19 AF XY: 0.0754 AC XY: 49310 AN XY: 653588

African (AFR) AF: 0.544 AC: 16349 AN: 30070

American (AMR) AF: 0.0678 AC: 2977 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 2292 AN: 24986

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38738

South Asian (SAS) AF: 0.0873 AC: 7232 AN: 82814

European-Finnish (FIN) AF: 0.0262 AC: 1336 AN: 50972

Middle Eastern (MID) AF: 0.130 AC: 707 AN: 5454

European-Non Finnish (NFE) AF: 0.0649 AC: 62812 AN: 967462

Other (OTH) AF: 0.0969 AC: 5319 AN: 54898

GnomAD4 genome AF: 0.194 AC: 29550 AN: 152234 Hom.: 6136 Cov.: 33 AF XY: 0.189 AC XY: 14086 AN XY: 74450

African (AFR) AF: 0.526 AC: 21815 AN: 41510

American (AMR) AF: 0.109 AC: 1665 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0915 AC: 317 AN: 3466

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.0956 AC: 462 AN: 4832

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10626

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0669 AC: 4547 AN: 67994

Other (OTH) AF: 0.159 AC: 336 AN: 2114

Alfa AF: 0.141 Hom.: 475

Bravo AF: 0.214

Asia WGS AF: 0.0860 AC: 299 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0040
DANN	Benign	0.75
PhyloP100		-3.1
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: rs9435269; hg19: chr1-6527745;