rs6863414

Variant names:

• chr5-137617888-T-C
• rs6863414
• NM_017415.3:c.*4210A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-137617888-T-C
• chr5-137617888-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017415.3(KLHL3):​c.*4210A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 152,034 control chromosomes in the GnomAD database, including 32,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32801 hom., cov: 31)
  • Exomes 𝑓: 0.70 (32 hom.)
• Consequence: KLHL3 NM_017415.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-137617888-T-C is Benign according to our data. Variant chr5-137617888-T-C is described in ClinVar as [Benign]. Clinvar id is 350923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3	c.*4210A>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.*4210A>G		3_prime_UTR_variant	Exon 15 of 15		NP_001244123.1
KLHL3	NM_001257195.2	c.*4210A>G		3_prime_UTR_variant	Exon 13 of 13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755	c.*4210A>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_017415.3	ENSP00000312397.4
KLHL3	ENST00000508657	c.*4210A>G		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000422099.1
KLHL3	ENST00000506491	c.*4210A>G		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000424828.1
KLHL3	ENST00000509694.1	n.623-24A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99336 AN: 151800 Hom.: 32789 Cov.: 31

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.674

GnomAD4 exome AF: 0.698 AC: 81 AN: 116 Hom.: 32 Cov.: 0 AF XY: 0.727 AC XY: 48 AN XY: 66

Gnomad4 FIN exome AF: 0.708

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.654 AC: 99392 AN: 151918 Hom.: 32801 Cov.: 31 AF XY: 0.659 AC XY: 48927 AN XY: 74270

Gnomad4 AFR AF: 0.597

Gnomad4 AMR AF: 0.665

Gnomad4 ASJ AF: 0.736

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.719

Gnomad4 FIN AF: 0.750

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.669

Alfa AF: 0.547 Hom.: 1349

Bravo AF: 0.639

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Pseudohypoaldosteronism type 2D Benign:1

Jan 12, 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:1

May 12, 2021

GeneDx

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	-0.93
CADD	Benign	0.22
DANN	Benign	0.38

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: rs6863414; hg19: chr5-136953577; COSMIC: COSV59050712; COSMIC: COSV59050712;