NM_017644.3:c.2T>C

Variant names:

• chr3-183650358-T-C
• rs1057515580
• NM_017644.3:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PS1_Moderate PM2 PP5_Moderate

The NM_017644.3(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 NM_017644.3 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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 29 codons. Genomic position: 183650441. Lost 0.047 part of the original CDS.
• PS1: Another start lost variant in NM_017644.3 (KLHL24) was described as [Pathogenic] in Lovd
• 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 rank	MANE	Protein	UniProt
KLHL24	NM_017644.3	c.2T>C	p.Met1?	start_lost	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	c.2T>C	p.Met1?	start_lost	Exon 3 of 8	1	NM_017644.3	ENSP00000242810.6

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

Feb 08, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Epidermolysis bullosa simplex, Koebner type Pathogenic:1

Aug 01, 2016

Lab of Molecular Dermatology, University Medical Center Freiburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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
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;