chr3-183650357-A-T

Variant names:

• chr3-183650357-A-T
• rs886037956
• NM_017644.3:c.1A>T
• KLHL24 p.Met1?

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_001349428.1(KLHL24):​c.-966A>T variant causes a 5 prime UTR premature start codon gain 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: "SCV000589964: 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).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL24 NM_001349428.1 5_prime_UTR_premature_start_codon_gain
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp, G2P
• cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies

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

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000589964: 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).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• 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_001349428.1. 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.1A>T	p.Met1?	initiator_codon	Exon 3 of 8	NP_060114.2	Q6TFL4-1
	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

Sel.	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	Q6TFL4-1
	KLHL24	ENST00000454652.6	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 4 of 9	ENSP00000395012.1	Q6TFL4-1
	KLHL24	ENST00000943871.1		c.1A>T	p.Met1?	initiator_codon	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	-	-	not provided (1)

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
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886037956;

hg19: chr3-183368145;