5-137628369-C-T

Variant names:

• chr5-137628369-C-T
• rs863225302
• NM_017415.3:c.1519G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017415.3(KLHL3):​c.1519G>A​(p.Val507Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL3 NM_017415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.91
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KLHL3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.9931 (below the threshold of 3.09). Trascript score misZ: 3.5661 (above the threshold of 3.09). GenCC associations: The gene is linked to pseudohypoaldosteronism type 2D.

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.1519G>A	p.Val507Ile	missense	Exon 13 of 15	NP_059111.2
	KLHL3	NM_001257194.1		c.1423G>A	p.Val475Ile	missense	Exon 13 of 15	NP_001244123.1
	KLHL3	NM_001257195.2		c.1273G>A	p.Val425Ile	missense	Exon 11 of 13	NP_001244124.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.1519G>A	p.Val507Ile	missense	Exon 13 of 15	ENSP00000312397.4
	KLHL3	ENST00000508657.5	TSL:1	c.1423G>A	p.Val475Ile	missense	Exon 13 of 15	ENSP00000422099.1
	KLHL3	ENST00000506491.5	TSL:1	c.1273G>A	p.Val425Ile	missense	Exon 11 of 13	ENSP00000424828.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
1	-	-	Pseudohypoaldosteronism type 2D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.19	T
Polyphen		0.91	P
Vest4		0.40
MutPred		0.58		Gain of ubiquitination at K505 (P = 0.1132)
MVP		0.62
MPC		0.60
ClinPred		0.79	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.22
Mutation Taster		=28/72	disease causing (ClinVar)

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: rs863225302; hg19: chr5-136964058; COSMIC: COSV59053989;