rs199469632

chr5-137637317-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S433G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHL3 NM_017415.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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, 3 uncertain in NM_017415.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant where missense usually causes diseases, KLHL3
• PP5: Variant 5-137637317-C-T is Pathogenic according to our data. Variant chr5-137637317-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30523.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.1298G>A	p.Ser433Asn	missense_variant	11/15	ENST00000309755.9
KLHL3	NM_001257194.1	c.1202G>A	p.Ser401Asn	missense_variant	11/15
KLHL3	NM_001257195.2	c.1052G>A	p.Ser351Asn	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL3	ENST00000309755.9	c.1298G>A	p.Ser433Asn	missense_variant	11/15	1	NM_017415.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pseudohypoaldosteronism type 2D Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 22, 2012

- -

Pseudohypoaldosteronism type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Richard Lifton Laboratory, Yale University School of Medicine

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.71	T;T;T;.
Polyphen		1.0, 0.99	.;.;D;D
Vest4		0.86
MutPred		0.55		.;.;Loss of phosphorylation at S433 (P = 0.0421);.;
MVP		0.65
MPC		1.6
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.84
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs199469632; hg19: chr5-136973006;