Variant 3-183650406-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The ENST00000242810.11(KLHL24):c.50G>A(p.Arg17His) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KLHL24
ENST00000242810.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

KLHL24 (HGNC:25947): (kelch like family member 24) The protein encoded by this gene is a ubiquitin ligase substrate receptor and is regulated by autoubiquitination. Variations in the translation initiation codon of this gene have been found, which result in an N-terminally truncated but more stable protein due to loss of the autoubiquitination function. The more stable mutant protein causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and the potentially life-threatening disease epidermolysis bullosa. The encoded protein is also involved in the regulation of kainate receptors. [provided by RefSeq, Mar 2017]

KLHL24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KLHL24. . Gene score misZ 2.8837 (greater than the threshold 3.09). Trascript score misZ 3.1276 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss.

BP4

Computational evidence support a benign effect (MetaRNN=0.27004594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL24	NM_017644.3 linkuse as main transcript	c.50G>A	p.Arg17His	missense_variant	3/8	ENST00000242810.11	NP_060114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL24	ENST00000242810.11 linkuse as main transcript	c.50G>A	p.Arg17His	missense_variant	3/8	1	NM_017644.3	ENSP00000242810	P1	Q6TFL4-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250542

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0000636

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.50G>A (p.R17H) alteration is located in exon 3 (coding exon 1) of the KLHL24 gene. This alteration results from a G to A substitution at nucleotide position 50, causing the arginine (R) at amino acid position 17 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.019

T;T;.;T;T;T;.;.;T;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

0.97

L;.;.;.;.;.;.;.;L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.84

N;N;D;N;D;N;N;N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.023

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.072

T;D;D;D;D;D;D;D;T;D;T

Polyphen

0.97

D;.;.;.;.;.;.;.;D;.;D

Vest4

0.41

MVP

0.81

MPC

1.1

ClinPred

0.24

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.59

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

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

Other links and lift over