5-137618759-CAAAA-CAA

Variant names:

• chr5-137618759-CAA-C
• rs58917494
• NM_017415.3:c.*3337_*3338delTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_017415.3(KLHL3):​c.*3337_*3338delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 110,520 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 22)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: KLHL3 NM_017415.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3	c.*3337_*3338delTT		3_prime_UTR_variant	Exon 15 of 15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.*3337_*3338delTT		3_prime_UTR_variant	Exon 15 of 15		NP_001244123.1
KLHL3	NM_001257195.2	c.*3337_*3338delTT		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.*3337_*3338delTT		3_prime_UTR_variant	Exon 15 of 15	1	NM_017415.3	ENSP00000312397.4
KLHL3	ENST00000508657	c.*3337_*3338delTT		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000422099.1
KLHL3	ENST00000506491	c.*3337_*3338delTT		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000424828.1
KLHL3	ENST00000509694.1	n.623-897_623-896delTT		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 58 AN: 110472 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000468

Gnomad ASJ AF: 0.00125

Gnomad EAS AF: 0.000918

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00243

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.167 AC: 1 AN: 6 Hom.: 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: 0.000525 AC: 58 AN: 110514 Hom.: 0 Cov.: 22 AF XY: 0.000528 AC XY: 28 AN XY: 52984

Gnomad4 AFR AF: 0.000342

Gnomad4 AMR AF: 0.000467

Gnomad4 ASJ AF: 0.00125

Gnomad4 EAS AF: 0.000920

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00243

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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;