1-6467651-G-A

Variant names:

• chr1-6467651-G-A
• rs78137382
• NM_020631.6:c.3012-79C>T

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.3012-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,518,896 control chromosomes in the GnomAD database, including 423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (41 hom., cov: 33)
  • Exomes 𝑓: 0.022 (382 hom.)
• Consequence: PLEKHG5 NM_020631.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.81
• Publications: 0 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 1-6467651-G-A is Benign according to our data. Variant chr1-6467651-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 676978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2527/152192) while in subpopulation NFE AF = 0.0256 (1738/67968). AF 95% confidence interval is 0.0246. There are 41 homozygotes in GnomAd4. There are 1182 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG5	NM_020631.6	c.3012-79C>T		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.3012-79C>T		intron_variant	Intron 20 of 20	2	NM_020631.6	ENSP00000366957.3

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2528 AN: 152074 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.0216 AC: 29527 AN: 1366704 Hom.: 382 Cov.: 21 AF XY: 0.0212 AC XY: 14519 AN XY: 684794

African (AFR) AF: 0.00335 AC: 106 AN: 31684

American (AMR) AF: 0.0123 AC: 547 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 446 AN: 25502

East Asian (EAS) AF: 0.00 AC: 0 AN: 39194

South Asian (SAS) AF: 0.00393 AC: 331 AN: 84270

European-Finnish (FIN) AF: 0.0116 AC: 602 AN: 52004

Middle Eastern (MID) AF: 0.0280 AC: 157 AN: 5604

European-Non Finnish (NFE) AF: 0.0256 AC: 26267 AN: 1026720

Other (OTH) AF: 0.0187 AC: 1071 AN: 57192

GnomAD4 genome AF: 0.0166 AC: 2527 AN: 152192 Hom.: 41 Cov.: 33 AF XY: 0.0159 AC XY: 1182 AN XY: 74422

African (AFR) AF: 0.00494 AC: 205 AN: 41530

American (AMR) AF: 0.0174 AC: 266 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.0110 AC: 117 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0256 AC: 1738 AN: 67968

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0194 Hom.: 7

Bravo AF: 0.0172

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Likely 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	-0.86
CADD	Benign	0.043
DANN	Benign	0.34
PhyloP100		-3.8
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: rs78137382; hg19: chr1-6527711;