rs2301708

Positions:

chr5-137634104-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.972

Variant links:

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]

KLHL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
KLHL3	NM_017415.3 linkuse as main transcript	c.1383G>A	p.Glu461=	synonymous_variant	12/15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1 linkuse as main transcript	c.1287G>A	p.Glu429=	synonymous_variant	12/15		NP_001244123.1
KLHL3	NM_001257195.2 linkuse as main transcript	c.1137G>A	p.Glu379=	synonymous_variant	10/13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9 linkuse as main transcript	c.1383G>A	p.Glu461=	synonymous_variant	12/15	1	NM_017415.3	ENSP00000312397	P1	Q9UH77-1

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27140

AN:

152106

Hom.:

2890

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.197

AC XY:

143062

AN XY:

727138

show subpopulations

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.:

AF XY:

0.187

AC XY:

13884

AN XY:

74422

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over