rs2301708

chr5-137634104-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017415.3(KLHL3):c.1383G>A(p.Glu461=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,898 control chromosomes in the GnomAD database, including 32,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2887 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29561 hom.)
• Consequence: KLHL3 NM_017415.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.972

Genes affected

KLHL3 (HGNC:6354): (kelch like family member 3) This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 5-137634104-C-T is Benign according to our data. Variant chr5-137634104-C-T is described in ClinVar as [Benign]. Clinvar id is 260807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137634104-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.972 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL3	NM_017415.3	c.1383G>A	p.Glu461=	synonymous_variant	12/15	ENST00000309755.9
KLHL3	NM_001257194.1	c.1287G>A	p.Glu429=	synonymous_variant	12/15
KLHL3	NM_001257195.2	c.1137G>A	p.Glu379=	synonymous_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL3	ENST00000309755.9	c.1383G>A	p.Glu461=	synonymous_variant	12/15	1	NM_017415.3	P1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27140 AN: 152106 Hom.: 2890 Cov.: 33

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.221 AC: 55610 AN: 251166 Hom.: 6964 AF XY: 0.219 AC XY: 29756 AN XY: 135718

Gnomad AFR exome AF: 0.0849

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.196 AC: 286756 AN: 1461674 Hom.: 29561 Cov.: 33 AF XY: 0.197 AC XY: 143062 AN XY: 727138

Gnomad4 AFR exome AF: 0.0840

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.392

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.178 AC: 27152 AN: 152224 Hom.: 2887 Cov.: 33 AF XY: 0.187 AC XY: 13884 AN XY: 74422

Gnomad4 AFR AF: 0.0888

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.175

Alfa AF: 0.181 Hom.: 5274

Bravo AF: 0.172

Asia WGS AF: 0.298 AC: 1036 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.172

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pseudohypoaldosteronism type 2D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	0.54

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: rs2301708; hg19: chr5-136969793; COSMIC: COSV59051876; COSMIC: COSV59051876;