5-137618759-CAAAA-CAAAAA

Variant names:

• chr5-137618759-C-CA
• rs58917494
• NM_017415.3:c.*3338dupT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_017415.3(KLHL3):​c.*3338dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 110,570 control chromosomes in the GnomAD database, including 58 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (58 hom., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLHL3 NM_017415.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0299 (3307/110570) while in subpopulation NFE AF= 0.0475 (2340/49222). AF 95% confidence interval is 0.0459. There are 58 homozygotes in gnomad4. There are 1462 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 58 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 3313 AN: 110528 Hom.: 58 Cov.: 22

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0137

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.00747

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0365

Gnomad NFE AF: 0.0476

Gnomad OTH AF: 0.0195

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0299 AC: 3307 AN: 110570 Hom.: 58 Cov.: 22 AF XY: 0.0276 AC XY: 1462 AN XY: 53026

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.00747

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.0264

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0475

Gnomad4 OTH AF: 0.0194

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;