chr3-183650358-T-C

Position:

• chr3-183650358-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The ENST00000242810.11(KLHL24):​c.2T>C​(p.Met1?) variant causes a start lost 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL24 ENST00000242810.11 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000242810.11 (KLHL24) was described as [Pathogenic] in ClinVar as 264648
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-183650358-T-C is Pathogenic according to our data. Variant chr3-183650358-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 370042.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL24	NM_017644.3	c.2T>C	p.Met1?	start_lost	3/8	ENST00000242810.11	NP_060114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL24	ENST00000242810.11	c.2T>C	p.Met1?	start_lost	3/8	1	NM_017644.3	ENSP00000242810	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 08, 2023

- -

Epidermolysis bullosa simplex, Koebner type Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Lab of Molecular Dermatology, University Medical Center Freiburg

Aug 01, 2016

This variant causes skin fragility as demonstrated by the correlation between genotype and phenotype in the family and functional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.;T;T;T;.;.;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.56	N;N;D;N;D;D;N;N;N;N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.72	P;.;.;.;.;.;.;.;P;.;P
Vest4		0.86
MutPred		0.91		Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);
MVP		0.95
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1057515580; hg19: chr3-183368146;