5-137692340-T-C

Variant names:

• chr5-137692340-T-C
• rs2905608
• NM_017415.3:c.471A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.98
• Publications: 21 publications found

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

ENSG00000295218 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.145).
• BP6: Variant 5-137692340-T-C is Benign according to our data. Variant chr5-137692340-T-C is described in ClinVar as Benign. ClinVar VariationId is 260809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.471A>G	p.Ala157Ala	synonymous_variant	Exon 5 of 15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.375A>G	p.Ala125Ala	synonymous_variant	Exon 5 of 15		NP_001244123.1
KLHL3	NM_001257195.2	c.225A>G	p.Ala75Ala	synonymous_variant	Exon 3 of 13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9	c.471A>G	p.Ala157Ala	synonymous_variant	Exon 5 of 15	1	NM_017415.3	ENSP00000312397.4

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118770 AN: 152082 Hom.: 46621 Cov.: 33

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

GnomAD2 exomes AF: 0.793 AC: 198470 AN: 250382 AF XY: 0.791

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 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.: 50 AF XY: 0.775 AC XY: 563216 AN XY: 726750

African (AFR) AF: 0.801 AC: 26807 AN: 33462

American (AMR) AF: 0.808 AC: 36066 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 18931 AN: 26128

East Asian (EAS) AF: 0.973 AC: 38642 AN: 39696

South Asian (SAS) AF: 0.811 AC: 69874 AN: 86202

European-Finnish (FIN) AF: 0.760 AC: 40603 AN: 53398

Middle Eastern (MID) AF: 0.748 AC: 4060 AN: 5430

European-Non Finnish (NFE) AF: 0.765 AC: 849943 AN: 1111642

Other (OTH) AF: 0.776 AC: 46837 AN: 60334

GnomAD4 genome AF: 0.781 AC: 118885 AN: 152200 Hom.: 46674 Cov.: 33 AF XY: 0.782 AC XY: 58211 AN XY: 74426

African (AFR) AF: 0.799 AC: 33203 AN: 41532

American (AMR) AF: 0.781 AC: 11951 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2523 AN: 3472

East Asian (EAS) AF: 0.984 AC: 5091 AN: 5176

South Asian (SAS) AF: 0.815 AC: 3933 AN: 4828

European-Finnish (FIN) AF: 0.759 AC: 8040 AN: 10592

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51747 AN: 67992

Other (OTH) AF: 0.766 AC: 1615 AN: 2108

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

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

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. -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-4.0
Mutation Taster		=69/31	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2905608; hg19: chr5-137028029; COSMIC: COSV59052799;