Genetic Variant KLHL24:p.Glu50Lys (chr3-183650504-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017644.3(KLHL24):c.148G>A(p.Glu50Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,854 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: not found (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: 9.60

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23283401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL24	NM_017644.3 link	c.148G>A	p.Glu50Lys	missense_variant	Exon 3 of 8	ENST00000242810.11	NP_060114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL24	ENST00000242810.11 link	c.148G>A	p.Glu50Lys	missense_variant	Exon 3 of 8	1	NM_017644.3	ENSP00000242810.6		Q6TFL4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251380

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148G>A (p.E50K) 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 148, causing the glutamic acid (E) at amino acid position 50 to be replaced by a lysine (K). 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

0.52

BayesDel_addAF

Benign

0.0069

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

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

Eigen

Benign

0.020

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.050

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.90

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

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.0

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

REVEL

Uncertain

0.33

Sift

Benign

0.23

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

Sift4G

Benign

0.85

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

Polyphen

0.049

B;.;.;.;.;.;.;.;B;.;P

Vest4

0.64

MutPred

0.39

Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);Gain of ubiquitination at E50 (P = 0.0114);

MVP

0.65

MPC

0.99

ClinPred

0.20

GERP RS

5.4

Varity_R

0.19

gMVP

0.76

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