rs199469639

Variant names:

• chr5-137639916-A-C
• rs199469639
• NM_017415.3:c.965T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_017415.3(KLHL3):​c.965T>G​(p.Phe322Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F322F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL3 NM_017415.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.99
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism type 2D

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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, 0.841
• PP5: Variant 5-137639916-A-C is Pathogenic according to our data. Variant chr5-137639916-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30516.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3	c.965T>G	p.Phe322Cys	missense_variant	Exon 9 of 15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.869T>G	p.Phe290Cys	missense_variant	Exon 9 of 15		NP_001244123.1
KLHL3	NM_001257195.2	c.719T>G	p.Phe240Cys	missense_variant	Exon 7 of 13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9	c.965T>G	p.Phe322Cys	missense_variant	Exon 9 of 15	1	NM_017415.3	ENSP00000312397.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pseudohypoaldosteronism type 2D Pathogenic:1

Jan 22, 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	0.89
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	2.9	.;.;M;.
PhyloP100		9.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.18	T;T;T;.
Polyphen		1.0	.;D;D;D
Vest4		0.89
MutPred		0.49		.;.;Loss of sheet (P = 0.0817);.;
MVP		0.82
MPC		2.0
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.83
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199469639; hg19: chr5-136975605;