rs199469635

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_017415.3(KLHL3):c.1582C>T(p.Arg528Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHL3
NM_017415.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.93

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 5-137628306-G-A is Pathogenic according to our data. Variant chr5-137628306-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 13 of 15	ENST00000309755.9	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1 link	c.1486C>T	p.Arg496Cys	missense_variant	Exon 13 of 15		NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2 link	c.1336C>T	p.Arg446Cys	missense_variant	Exon 11 of 13		NP_001244124.1	Q9UH77-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 13 of 15	1	NM_017415.3	ENSP00000312397.4		Q9UH77-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00209

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2D

Pathogenic:3

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pseudohypoaldosteronism type 2A

Pathogenic:1

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

.;.;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.93

.;.;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Uncertain

0.58

Sift

Benign

0.047

D;D;D

Sift4G

Uncertain

0.0070

D;T;D

Polyphen

1.0

.;.;D

Vest4

0.92

MutPred

0.71

.;.;Loss of MoRF binding (P = 0.0508);

MVP

0.82

MPC

1.9

ClinPred

1.0

GERP RS

5.5

Varity_R

0.81

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over