rs199469635

chr5-137628306-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHL3 NM_017415.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.93

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a repeat Kelch 5 (size 46) in uniprot entity KLHL3_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 chr5-137628305-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KLHL3
• 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/exons	MANE	UniProt
KLHL3	NM_017415.3	c.1582C>T	p.Arg528Cys	missense_variant	13/15	ENST00000309755.9
KLHL3	NM_001257194.1	c.1486C>T	p.Arg496Cys	missense_variant	13/15
KLHL3	NM_001257195.2	c.1336C>T	p.Arg446Cys	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL3	ENST00000309755.9	c.1582C>T	p.Arg528Cys	missense_variant	13/15	1	NM_017415.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

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.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudohypoaldosteronism type 2D Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 11, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 11, 2022	- -

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	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.92	D
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	D
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

Other links and lift over

dbSNP: rs199469635; hg19: chr5-136963995;