rs17171525

chr5-137625877-C-Achr5-137625877-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017415.3(KLHL3):c.1611G>T(p.Gly537=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.184

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 -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	UniProt
KLHL3	NM_017415.3	c.1611G>T	p.Gly537=	synonymous_variant	14/15	ENST00000309755.9
KLHL3	NM_001257194.1	c.1515G>T	p.Gly505=	synonymous_variant	14/15
KLHL3	NM_001257195.2	c.1365G>T	p.Gly455=	synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL3	ENST00000309755.9	c.1611G>T	p.Gly537=	synonymous_variant	14/15	1	NM_017415.3	P1

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5524 AN: 152186 Hom.: 218 Cov.: 32

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

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.: 32 AF XY: 0.0403 AC XY: 29328 AN XY: 727222

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.: 32 AF XY: 0.0364 AC XY: 2712 AN XY: 74488

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: 47 AN: 3478

EpiCase AF: 0.0360

EpiControl AF: 0.0332

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

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

Other links and lift over

dbSNP: rs17171525; hg19: chr5-136961566; COSMIC: COSV59059161;