KLHL3 p.Glu461Glu

Variant names:

• chr5-137634103-G-G
• NM_017415.3:c.

Your query was ambiguous. Multiple possible variants found:

• chr5-137634104--
• chr5-137634104-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017415.3(KLHL3):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL3 NM_017415.3 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.972
• Publications: 0 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), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.		exon_region	Exon 12 of 15	NP_059111.2	Q9UH77-1
	KLHL3	NM_001257194.1		c.		exon_region	Exon 12 of 15	NP_001244123.1	Q9UH77-2
	KLHL3	NM_001257195.2		c.		exon_region	Exon 10 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.		exon_region	Exon 12 of 15	ENSP00000312397.4	Q9UH77-1
	KLHL3	ENST00000508657.5	TSL:1	c.		exon_region	Exon 12 of 15	ENSP00000422099.1	Q9UH77-2
	KLHL3	ENST00000506491.5	TSL:1	c.		exon_region	Exon 10 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-136969792;