3-183650946-A-C

Position:

chr3-183650946-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000242810.11(KLHL24):c.590A>C(p.Asp197Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,614,214 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 4 hom. )

Consequence

KLHL24
ENST00000242810.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.95

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 Benign. Variant got -19 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=0.0114785135).

BP6

Variant 3-183650946-A-C is Benign according to our data. Variant chr3-183650946-A-C is described in ClinVar as [Benign]. Clinvar id is 1601787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00104 (159/152330) while in subpopulation EAS AF= 0.0166 (86/5188). AF 95% confidence interval is 0.0137. There are 4 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL24	NM_017644.3 linkuse as main transcript	c.590A>C	p.Asp197Ala	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.590A>C	p.Asp197Ala	missense_variant	3/8	1	NM_017644.3	ENSP00000242810	P1	Q6TFL4-1
KLHL24	ENST00000454652.6 linkuse as main transcript	c.590A>C	p.Asp197Ala	missense_variant	4/9	1		ENSP00000395012	P1	Q6TFL4-1
KLHL24	ENST00000476808.1 linkuse as main transcript	c.590A>C	p.Asp197Ala	missense_variant	1/5	2		ENSP00000419010		Q6TFL4-2
KLHL24	ENST00000475827.5 linkuse as main transcript	n.152-12512A>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0169

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00201

AC:

505

AN:

251098

Hom.:

AF XY:

0.00220

AC XY:

299

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0151

Gnomad SAS exome

AF:

0.00630

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000752

AC:

1100

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

674

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00874

Gnomad4 SAS exome

AF:

0.00685

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00104

AC:

159

AN:

152330

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0166

Gnomad4 SAS

AF:

0.00891

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000493

Hom.:

Bravo

AF:

0.000808

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00194

AC:

235

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T;.

Eigen

Benign

0.031

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.0

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Uncertain

0.35

Sift

Benign

0.046

D;D;D

Sift4G

Benign

0.091

T;T;T

Polyphen

0.062

B;B;B

Vest4

0.52

MVP

0.71

MPC

1.1

ClinPred

0.037

GERP RS

5.3

Varity_R

0.51

gMVP

0.42

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