5-137618759-CA-C

Position:

• chr5-137618759-CA-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000309755.9(KLHL3):​c.*3338del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 110,434 control chromosomes in the GnomAD database, including 3,443 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (3443 hom., cov: 22)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: KLHL3 ENST00000309755.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.572

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 -10 ACMG points.

• BP6: Variant 5-137618759-CA-C is Benign according to our data. Variant chr5-137618759-CA-C is described in ClinVar as [Benign]. Clinvar id is 350931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL3	NM_017415.3	c.*3338del		3_prime_UTR_variant	15/15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.*3338del		3_prime_UTR_variant	15/15		NP_001244123.1
KLHL3	NM_001257195.2	c.*3338del		3_prime_UTR_variant	13/13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9	c.*3338del		3_prime_UTR_variant	15/15	1	NM_017415.3	ENSP00000312397	P1
KLHL3	ENST00000506491.5	c.*3338del		3_prime_UTR_variant	13/13	1		ENSP00000424828
KLHL3	ENST00000508657.5	c.*3338del		3_prime_UTR_variant	15/15	1		ENSP00000422099
KLHL3	ENST00000509694.1	n.623-896del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.245 AC: 27018 AN: 110384 Hom.: 3449 Cov.: 22

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.0342

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.0714

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.141

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.167 AC: 1 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.245 AC: 27016 AN: 110428 Hom.: 3443 Cov.: 22 AF XY: 0.253 AC XY: 13388 AN XY: 52952

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.0714

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.361

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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: rs58917494; hg19: chr5-136954448;