Variant chr5-137638979-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_017415.3(KLHL3):c.1193C>T(p.Ala398Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHL3
NM_017415.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 10.0

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL3. . Gene score misZ 2.9931 (greater than the threshold 3.09). Trascript score misZ 3.5661 (greater than threshold 3.09). GenCC has associacion of gene with pseudohypoaldosteronism type 2D.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

PP5

Variant 5-137638979-G-A is Pathogenic according to our data. Variant chr5-137638979-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31544.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL3	NM_017415.3 linkuse as main transcript	c.1193C>T	p.Ala398Val	missense_variant	10/15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1 linkuse as main transcript	c.1097C>T	p.Ala366Val	missense_variant	10/15		NP_001244123.1
KLHL3	NM_001257195.2 linkuse as main transcript	c.947C>T	p.Ala316Val	missense_variant	8/13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9 linkuse as main transcript	c.1193C>T	p.Ala398Val	missense_variant	10/15	1	NM_017415.3	ENSP00000312397	P1	Q9UH77-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2D

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 11, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

.;.;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.49

.;.;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.021

D;D;D;D

Sift4G

Benign

0.070

T;T;T;.

Polyphen

1.0, 1.0, 1.0

.;D;D;D

Vest4

0.91

MutPred

0.59

.;.;Loss of phosphorylation at Y397 (P = 0.2173);.;

MVP

0.77

MPC

1.5

ClinPred

0.98

GERP RS

4.8

Varity_R

0.77

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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