rs2301708

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017415.3(KLHL3):c.1383G>A(p.Glu461Glu) 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

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

pseudohypoaldosteronism type 2D
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

KLHL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 260807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
KLHL3	NM_017415.3 link	c.1383G>A	p.Glu461Glu	synonymous_variant	Exon 12 of 15	ENST00000309755.9	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1 link	c.1287G>A	p.Glu429Glu	synonymous_variant	Exon 12 of 15		NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2 link	c.1137G>A	p.Glu379Glu	synonymous_variant	Exon 10 of 13		NP_001244124.1	Q9UH77-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9 link	c.1383G>A	p.Glu461Glu	synonymous_variant	Exon 12 of 15	1	NM_017415.3	ENSP00000312397.4		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

GnomAD2 exomes

AF:

0.221

AC:

55610

AN:

251166

AF XY:

0.219

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 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

African (AFR)

AF:

0.0840

AC:

2813

AN:

33478

American (AMR)

AF:

0.269

AC:

12037

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

4576

AN:

26128

East Asian (EAS)

AF:

0.392

AC:

15548

AN:

39690

South Asian (SAS)

AF:

0.237

AC:

20463

AN:

86232

European-Finnish (FIN)

AF:

0.243

AC:

12968

AN:

53390

Middle Eastern (MID)

AF:

0.100

AC:

574

AN:

5738

European-Non Finnish (NFE)

AF:

0.186

AC:

206289

AN:

1111934

Other (OTH)

AF:

0.190

AC:

11488

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

12782

25564

38347

51129

63911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7428

14856

22284

29712

37140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.178

AC:

27152

AN:

152224

Hom.:

2887

Cov.:

AF XY:

0.187

AC XY:

13884

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0888

AC:

3689

AN:

41560

American (AMR)

AF:

0.229

AC:

3508

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

625

AN:

3470

East Asian (EAS)

AF:

0.407

AC:

2104

AN:

5174

South Asian (SAS)

AF:

0.250

AC:

1208

AN:

4824

European-Finnish (FIN)

AF:

0.266

AC:

2816

AN:

10596

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.188

AC:

12756

AN:

67988

Other (OTH)

AF:

0.175

AC:

369

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1111

2223

3334

4446

5557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.182

Hom.:

11601

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

Aug 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant pseudohypoaldosteronism type 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoaldosteronism type 2D

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.54

PhyloP100

0.97

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over