5-137618889-AT-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_017415.3(KLHL3):c.*3208del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (13 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: KLHL3 NM_017415.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0910

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00466 (674/144676) while in subpopulation AFR AF= 0.0117 (462/39374). AF 95% confidence interval is 0.0109. There are 13 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL3	NM_017415.3	c.*3208del		3_prime_UTR_variant	15/15	ENST00000309755.9
KLHL3	NM_001257194.1	c.*3208del		3_prime_UTR_variant	15/15
KLHL3	NM_001257195.2	c.*3208del		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL3	ENST00000309755.9	c.*3208del		3_prime_UTR_variant	15/15	1	NM_017415.3	P1
KLHL3	ENST00000506491.5	c.*3208del		3_prime_UTR_variant	13/13	1
KLHL3	ENST00000508657.5	c.*3208del		3_prime_UTR_variant	15/15	1
KLHL3	ENST00000509694.1	n.623-1026del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 669 AN: 144650 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00205

Gnomad EAS AF: 0.00279

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00551

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00466 AC: 674 AN: 144676 Hom.: 13 Cov.: 0 AF XY: 0.00452 AC XY: 316 AN XY: 69984

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.00313

Gnomad4 ASJ AF: 0.00205

Gnomad4 EAS AF: 0.00280

Gnomad4 SAS AF: 0.000218

Gnomad4 FIN AF: 0.00187

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00547

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Uncertain:1

Uncertain significance, 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: rs369833337; hg19: chr5-136954578;