rs1057515580

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PS1_Moderate PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV000328619: This variant causes skin fragility as demonstrated by the correlation between genotype and phenotype in the family and functional studies.".

• 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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex 6, generalized, with scarring and hair loss

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 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 ClinVar
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000328619: This variant causes skin fragility as demonstrated by the correlation between genotype and phenotype in the family and functional studies.
• 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 VariationId is 370042.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017644.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL24	NM_017644.3	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 3 of 8	NP_060114.2	Q6TFL4-1
	KLHL24	NM_001349413.1		c.2T>C	p.Met1?	start_lost	Exon 3 of 9	NP_001336342.1
	KLHL24	NM_001349414.1		c.2T>C	p.Met1?	start_lost	Exon 3 of 9	NP_001336343.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL24	ENST00000242810.11	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 3 of 8	ENSP00000242810.6	Q6TFL4-1
	KLHL24	ENST00000454652.6	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 4 of 9	ENSP00000395012.1	Q6TFL4-1
	KLHL24	ENST00000943871.1		c.2T>C	p.Met1?	start_lost	Exon 3 of 10	ENSP00000613930.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss (1)
1	-	-	Epidermolysis bullosa simplex, Koebner type (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.44	D
PhyloP100		7.5
PROVEAN	Benign	-0.56	N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.72	P
Vest4		0.86
MutPred		0.91		Gain of catalytic residue at M1 (P = 0.0059)
MVP		0.95
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.89
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057515580; hg19: chr3-183368146;