5-137618759-CAAAA-CAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_017415.3(KLHL3):​c.*3338delT 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 NM_017415.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.572
• Publications: 1 publications found

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]

KLHL3 Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism type 2D

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017415.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	NM_017415.3	MANE Select	c.*3338delT		3_prime_UTR	Exon 15 of 15	NP_059111.2	Q9UH77-1
	KLHL3	NM_001257194.1		c.*3338delT		3_prime_UTR	Exon 15 of 15	NP_001244123.1	Q9UH77-2
	KLHL3	NM_001257195.2		c.*3338delT		3_prime_UTR	Exon 13 of 13	NP_001244124.1	Q9UH77-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.*3338delT		3_prime_UTR	Exon 15 of 15	ENSP00000312397.4	Q9UH77-1
	KLHL3	ENST00000508657.5	TSL:1	c.*3338delT		3_prime_UTR	Exon 15 of 15	ENSP00000422099.1	Q9UH77-2
	KLHL3	ENST00000506491.5	TSL:1	c.*3338delT		3_prime_UTR	Exon 13 of 13	ENSP00000424828.1	Q9UH77-3

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.399 AC: 12790 AN: 32078

American (AMR) AF: 0.269 AC: 2878 AN: 10698

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 172 AN: 2408

East Asian (EAS) AF: 0.487 AC: 2114 AN: 4340

South Asian (SAS) AF: 0.361 AC: 1338 AN: 3706

European-Finnish (FIN) AF: 0.154 AC: 880 AN: 5730

Middle Eastern (MID) AF: 0.128 AC: 23 AN: 180

European-Non Finnish (NFE) AF: 0.131 AC: 6458 AN: 49210

Other (OTH) AF: 0.230 AC: 343 AN: 1494

Alfa AF: 0.0266 Hom.: 15

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs58917494; hg19: chr5-136954448;