dbSNP rs199469632: KLHL3:p.Ser433Asn (chr5-137637317-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP2PP3PP5_Moderate

The NM_017415.3(KLHL3):c.1298G>A(p.Ser433Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

KLHL3
NM_017415.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.91

Publications

11 publications found

Variant links:

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

KLHL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_017415.3

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.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-137637317-C-T is Pathogenic according to our data. Variant chr5-137637317-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30523.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHL3	NM_017415.3	MANE Select	c.1298G>A	p.Ser433Asn	missense	Exon 11 of 15	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1		c.1202G>A	p.Ser401Asn	missense	Exon 11 of 15	NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2		c.1052G>A	p.Ser351Asn	missense	Exon 9 of 13	NP_001244124.1	Q9UH77-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.1298G>A	p.Ser433Asn	missense	Exon 11 of 15	ENSP00000312397.4	Q9UH77-1
KLHL3	ENST00000508657.5	TSL:1	c.1202G>A	p.Ser401Asn	missense	Exon 11 of 15	ENSP00000422099.1	Q9UH77-2
KLHL3	ENST00000506491.5	TSL:1	c.1052G>A	p.Ser351Asn	missense	Exon 9 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pseudohypoaldosteronism type 2D (2)

Pseudohypoaldosteronism type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.38

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.43

Sift

Benign

0.18

Sift4G

Benign

0.71

Polyphen

1.0

Vest4

0.86

MutPred

0.55

Loss of phosphorylation at S433 (P = 0.0421)

MVP

0.65

MPC

1.6

ClinPred

0.98

GERP RS

4.9

Varity_R

0.84

gMVP

0.89

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.52

Position offset: -1

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over