rs3007421

Positions:

• chr1-6470129-G-A
• chr1-6470129-G-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.1800+107C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,258,266 control chromosomes in the GnomAD database, including 13,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2974 hom., cov: 33)
  • Exomes 𝑓: 0.13 (10059 hom.)
• Consequence: PLEKHG5 NM_020631.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.956

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=-0.83).
• BP6: Variant 1-6470129-G-A is Benign according to our data. Variant chr1-6470129-G-A is described in ClinVar as [Benign]. Clinvar id is 667938.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-6470129-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG5	NM_020631.6	c.1800+107C>T		intron_variant		ENST00000377728.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG5	ENST00000377728.8	c.1800+107C>T		intron_variant		2	NM_020631.6	P2

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26812 AN: 152064 Hom.: 2961 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.164

GnomAD4 exome AF: 0.126 AC: 139643 AN: 1106084 Hom.: 10059 AF XY: 0.127 AC XY: 70912 AN XY: 557104

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.0826

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.00784

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.177 AC: 26867 AN: 152182 Hom.: 2974 Cov.: 33 AF XY: 0.175 AC XY: 13029 AN XY: 74398

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.166

Alfa AF: 0.130 Hom.: 837

Bravo AF: 0.183

Asia WGS AF: 0.116 AC: 403 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 14, 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	-0.83
CADD	Benign	6.1
DANN	Benign	0.49

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: rs3007421; hg19: chr1-6530189;