3-183650427-G-A

Position:

chr3-183650427-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_017644.3(KLHL24):c.71G>A(p.Arg24Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KLHL24
NM_017644.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.73

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:

KLHL24 (HGNC:):

KLHL24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL24	NM_017644.3 linkuse as main transcript	c.71G>A	p.Arg24Gln	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.71G>A	p.Arg24Gln	missense_variant	3/8	1	NM_017644.3	ENSP00000242810.6		Q6TFL4-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251092

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Mar 14, 2023

The c.71G>A (p.R24Q) 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 71, causing the arginine (R) at amino acid position 24 to be replaced by a glutamine (Q). 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

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.017

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.44

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

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.0

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

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.14

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

REVEL

Uncertain

0.32

Sift

Benign

0.051

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

Sift4G

Benign

0.48

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

Polyphen

0.97

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

Vest4

0.48

MutPred

0.34

Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);Gain of ubiquitination at K25 (P = 0.0476);

MVP

0.81

MPC

0.79

ClinPred

0.46

GERP RS

5.6

Varity_R

0.15

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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