1-6467685-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -3.10

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=-0.89).
• 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_single_submitter, 1 stars. Variant chr1-6467685-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.3012-113G>A		intron_variant		ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.3012-113G>A		intron_variant		2	NM_020631.6	P2

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

Gnomad4 AFR exome AF: 0.544

Gnomad4 AMR exome AF: 0.0678

Gnomad4 ASJ exome AF: 0.0917

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.0873

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0649

Gnomad4 OTH exome AF: 0.0969

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

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0915

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0956

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.0669

Gnomad4 OTH AF: 0.159

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 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	-0.89
Cadd	Benign	0.0040
Dann	Benign	0.75

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: rs9435269; hg19: chr1-6527745;