5-137692340-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017415.3(KLHL3):c.471A>G(p.Ala157Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 1,613,152 control chromosomes in the GnomAD database, including 486,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 46674 hom., cov: 33)

Exomes 𝑓: 0.77 ( 439693 hom. )

Consequence

KLHL3
NM_017415.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.98

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 5-137692340-T-C is Benign according to our data. Variant chr5-137692340-T-C is described in ClinVar as [Benign]. Clinvar id is 260809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-137692340-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.98 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3 link	c.471A>G	p.Ala157Ala	synonymous_variant	Exon 5 of 15	ENST00000309755.9	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1 link	c.375A>G	p.Ala125Ala	synonymous_variant	Exon 5 of 15		NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2 link	c.225A>G	p.Ala75Ala	synonymous_variant	Exon 3 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.471A>G	p.Ala157Ala	synonymous_variant	Exon 5 of 15	1	NM_017415.3	ENSP00000312397.4		Q9UH77-1

Frequencies

GnomAD3 genomes

AF:

0.781

AC:

118770

AN:

152082

Hom.:

46621

Cov.:

show subpopulations

Gnomad AFR

AF:

0.799

Gnomad AMI

AF:

0.627

Gnomad AMR

AF:

0.781

Gnomad ASJ

AF:

0.727

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.815

Gnomad FIN

AF:

0.759

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.763

GnomAD3 exomes

AF:

0.793

AC:

198470

AN:

250382

Hom.:

79109

AF XY:

0.791

AC XY:

106974

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.803

Gnomad AMR exome

AF:

0.809

Gnomad ASJ exome

AF:

0.730

Gnomad EAS exome

AF:

0.991

Gnomad SAS exome

AF:

0.812

Gnomad FIN exome

AF:

0.758

Gnomad NFE exome

AF:

0.762

Gnomad OTH exome

AF:

0.764

GnomAD4 exome

AF:

0.775

AC:

1131763

AN:

1460952

Hom.:

439693

Cov.:

AF XY:

0.775

AC XY:

563216

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.801

Gnomad4 AMR exome

AF:

0.808

Gnomad4 ASJ exome

AF:

0.725

Gnomad4 EAS exome

AF:

0.973

Gnomad4 SAS exome

AF:

0.811

Gnomad4 FIN exome

AF:

0.760

Gnomad4 NFE exome

AF:

0.765

Gnomad4 OTH exome

AF:

0.776

GnomAD4 genome

AF:

0.781

AC:

118885

AN:

152200

Hom.:

46674

Cov.:

AF XY:

0.782

AC XY:

58211

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.799

Gnomad4 AMR

AF:

0.781

Gnomad4 ASJ

AF:

0.727

Gnomad4 EAS

AF:

0.984

Gnomad4 SAS

AF:

0.815

Gnomad4 FIN

AF:

0.759

Gnomad4 NFE

AF:

0.761

Gnomad4 OTH

AF:

0.766

Alfa

AF:

0.749

Hom.:

14982

Bravo

AF:

0.784

Asia WGS

AF:

0.866

AC:

3012

AN:

3478

EpiCase

AF:

0.766

EpiControl

AF:

0.758

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala157Ala in exon 5 of KLHL3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 99.06% (8557/8638) o f East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs2905608). -

Pseudohypoaldosteronism type 2D

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0070

DANN

Benign

0.74

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