rs387907156
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_017415.3(KLHL3):c.1277C>T(p.Pro426Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,072 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: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
KLHL3
NM_017415.3 missense
NM_017415.3 missense
Scores
11
4
2
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_017415.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, KLHL3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.8
PP5
?
Variant 5-137637338-G-A is Pathogenic according to our data. Variant chr5-137637338-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31546.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL3 | NM_017415.3 | c.1277C>T | p.Pro426Leu | missense_variant | 11/15 | ENST00000309755.9 | |
KLHL3 | NM_001257194.1 | c.1181C>T | p.Pro394Leu | missense_variant | 11/15 | ||
KLHL3 | NM_001257195.2 | c.1031C>T | p.Pro344Leu | missense_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL3 | ENST00000309755.9 | c.1277C>T | p.Pro426Leu | missense_variant | 11/15 | 1 | NM_017415.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251448Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135902
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727198
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74464
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;D;D
Sift4G
Uncertain
D;T;T;.
Polyphen
1.0, 0.97
.;.;D;D
Vest4
MutPred
0.66
.;.;Gain of MoRF binding (P = 0.0606);.;
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at