rs17171525

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1611G>T(p.Gly537Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,614,148 control chromosomes in the GnomAD database, including 2,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 221 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1850 hom. )

Consequence

KLHL3
NM_017415.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.184

Publications

6 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=-0.24).

BP6

Variant 5-137625877-C-A is Benign according to our data. Variant chr5-137625877-C-A is described in ClinVar as Benign. ClinVar VariationId is 260808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.184 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KLHL3	NM_017415.3 link	c.1611G>T	p.Gly537Gly	synonymous_variant	Exon 14 of 15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1 link	c.1515G>T	p.Gly505Gly	synonymous_variant	Exon 14 of 15		NP_001244123.1
KLHL3	NM_001257195.2 link	c.1365G>T	p.Gly455Gly	synonymous_variant	Exon 12 of 13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9 link	c.1611G>T	p.Gly537Gly	synonymous_variant	Exon 14 of 15	1	NM_017415.3	ENSP00000312397.4

Frequencies

GnomAD3 genomes

AF:

0.0363

AC:

5524

AN:

152186

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.0198

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0422

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0484

AC:

12160

AN:

251402

AF XY:

0.0429

show subpopulations

Gnomad AFR exome

AF:

0.00966

Gnomad AMR exome

AF:

0.178

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.000652

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0386

GnomAD4 exome

AF:

0.0420

AC:

61351

AN:

1461844

Hom.:

1850

Cov.:

AF XY:

0.0403

AC XY:

29328

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00789

AC:

264

AN:

33480

American (AMR)

AF:

0.171

AC:

7629

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0223

AC:

583

AN:

26136

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.0184

AC:

1587

AN:

86258

European-Finnish (FIN)

AF:

0.0233

AC:

1246

AN:

53416

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0430

AC:

47859

AN:

1111966

Other (OTH)

AF:

0.0353

AC:

2130

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2973

5946

8920

11893

14866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1894

3788

5682

7576

9470

<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:

0.0363

AC:

5533

AN:

152304

Hom.:

221

Cov.:

AF XY:

0.0364

AC XY:

2712

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0113

AC:

470

AN:

41554

American (AMR)

AF:

0.114

AC:

1739

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0157

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0198

AC:

210

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0422

AC:

2869

AN:

68026

Other (OTH)

AF:

0.0425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

270

540

810

1080

1350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0389

Hom.:

500

Bravo

AF:

0.0430

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0360

EpiControl

AF:

0.0332

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2019

GeneDx

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

-0.24

CADD

Benign

7.5

(source)

DANN

Benign

0.67

PhyloP100

0.18

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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