5-137692340-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017415.3(KLHL3):c.471A>G(p.Ala157=) 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

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]

ACMG classification

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/exons	MANE	UniProt
KLHL3	NM_017415.3	c.471A>G	p.Ala157=	synonymous_variant	5/15	ENST00000309755.9
KLHL3	NM_001257194.1	c.375A>G	p.Ala125=	synonymous_variant	5/15
KLHL3	NM_001257195.2	c.225A>G	p.Ala75=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL3	ENST00000309755.9	c.471A>G	p.Ala157=	synonymous_variant	5/15	1	NM_017415.3	P1

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

GnomAD3 exomes AF: 0.793 AC: 198470 AN: 250382 Hom.: 79109 AF XY: 0.791 AC XY: 106974 AN XY: 135306

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

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.: 33 AF XY: 0.782 AC XY: 58211 AN XY: 74426

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

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Other links and lift over

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