rs17171525

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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:

KLHL3 (HGNC:):

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=-0.24).

BP6

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

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/exons	MANE	Protein	UniProt
KLHL3	NM_017415.3 linkuse as main transcript	c.1611G>T	p.Gly537Gly	synonymous_variant	14/15	ENST00000309755.9	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1 linkuse as main transcript	c.1515G>T	p.Gly505Gly	synonymous_variant	14/15		NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2 linkuse as main transcript	c.1365G>T	p.Gly455Gly	synonymous_variant	12/13		NP_001244124.1	Q9UH77-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9 linkuse as main transcript	c.1611G>T	p.Gly537Gly	synonymous_variant	14/15	1	NM_017415.3	ENSP00000312397.4		Q9UH77-1

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

GnomAD3 exomes

AF:

0.0484

AC:

12160

AN:

251402

Hom.:

736

AF XY:

0.0429

AC XY:

5831

AN XY:

135872

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 SAS exome

AF:

0.0180

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

Gnomad4 AFR exome

AF:

0.00789

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.0223

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0184

Gnomad4 FIN exome

AF:

0.0233

Gnomad4 NFE exome

AF:

0.0430

Gnomad4 OTH exome

AF:

0.0353

GnomAD4 genome

AF:

0.0363

AC:

5533

AN:

152304

Hom.:

221

Cov.:

AF XY:

0.0364

AC XY:

2712

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0113

Gnomad4 AMR

AF:

0.114

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0157

Gnomad4 FIN

AF:

0.0198

Gnomad4 NFE

AF:

0.0422

Gnomad4 OTH

AF:

0.0425

Alfa

AF:

0.0368

Hom.:

219

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

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

-0.24

CADD

Benign

7.5

DANN

Benign

0.67

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

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