1-6467651-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -3.81

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 stars. Variant chr1-6467651-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.3012-79C>T		intron_variant		ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.3012-79C>T		intron_variant		2	NM_020631.6	P2

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

Gnomad4 AFR exome AF: 0.00335

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00393

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0187

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

Gnomad4 AFR AF: 0.00494

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0180

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs78137382; hg19: chr1-6527711;