3-183650357-A-T

Variant names:

• chr3-183650357-A-T
• rs886037956
• NM_017644.3:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Strong PS1_Moderate PM2 PP5_Moderate

The NM_017644.3(KLHL24):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.70
• Publications: 10 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, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 10 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-183650357-A-T is Pathogenic according to our data. Variant chr3-183650357-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 432253.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL24	NM_017644.3	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 8	NP_060114.2
	KLHL24	NM_001349428.1		c.-966A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001336357.1
	KLHL24	NM_001349429.1		c.-966A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001336358.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL24	ENST00000242810.11	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 8	ENSP00000242810.6
	KLHL24	ENST00000454652.6	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 4 of 9	ENSP00000395012.1
	KLHL24	ENST00000476808.1	TSL:2	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000419010.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 17, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1 A>T variant in the KLHL24 gene has not been reported previously, however a different base pair substitution involving the initiation codon (c.1 A>G) is a common variant associated with generalized epidermolysis bullosa simplex (Lin et al., 2016; He et al., 2016). The c.1 A>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1 A>T variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. However, it has been shown that a downstream in frame Met initiation codon is used to initiate translation of a protein truncated by deletion of the initial 28 amino acids of the KLHL24 (KLHL24delta28) protein product in some patients (Lin et al., 2016; He et al., 2016). This protein was more stable than the normal protein and lead to increased ubiquitination and turnover of keratin 14. The pathobiology of Met1? in KLHL24 was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, the mutant was found to be associated with intermediate filament abnormalities in keratinocytes and fibroblasts (He et al., 2016). Therefore, KLHL24 pathogenic variants were described as a cause of skin fragility through regulation of turnover of keratin 14 and demonstrate that the KLHL24 protein plays a role in maintaining the balance between intermediate filament stability and degradation required for skin integrity. We interpret the c.1 A>T variant as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.10	D
PhyloP100		8.7
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.17	B
Vest4		0.75
MutPred		0.90		Loss of MoRF binding (P = 0.0765)
MVP		0.90
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.020	Neutral
Varity_R		0.79
gMVP		0.74
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037956; hg19: chr3-183368145;