1-6467455-C-T

Variant names:

• chr1-6467455-C-T
• rs11800788
• NM_020631.6:c.*108G>A

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.*108G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,107,080 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (5 hom.)
• Consequence: PLEKHG5 NM_020631.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.63
• 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=-0.9).
• BP6: Variant 1-6467455-C-T is Benign according to our data. Variant chr1-6467455-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 297930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00715 (1089/152338) while in subpopulation AFR AF = 0.0253 (1051/41574). AF 95% confidence interval is 0.024. There are 9 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.*108G>A		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.*108G>A		3_prime_UTR_variant	Exon 21 of 21	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 1086 AN: 152220 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000772 AC: 737 AN: 954742 Hom.: 5 Cov.: 13 AF XY: 0.000598 AC XY: 297 AN XY: 496346

African (AFR) AF: 0.0249 AC: 590 AN: 23698

American (AMR) AF: 0.00125 AC: 55 AN: 44092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22978

East Asian (EAS) AF: 0.0000801 AC: 3 AN: 37450

South Asian (SAS) AF: 0.0000263 AC: 2 AN: 76178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50494

Middle Eastern (MID) AF: 0.000636 AC: 3 AN: 4718

European-Non Finnish (NFE) AF: 0.0000338 AC: 22 AN: 651378

Other (OTH) AF: 0.00142 AC: 62 AN: 43756

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152338 Hom.: 9 Cov.: 33 AF XY: 0.00651 AC XY: 485 AN XY: 74500

African (AFR) AF: 0.0253 AC: 1051 AN: 41574

American (AMR) AF: 0.00176 AC: 27 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00707 Hom.: 4

Bravo AF: 0.00822

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely 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

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.81
PhyloP100		-5.6
Mutation Taster		=100/0	polymorphism

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: rs11800788; hg19: chr1-6527515;