NM_017644.3:c.367T>C

Variant names:

• chr3-183650723-T-C
• NM_017644.3:c.367T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017644.3(KLHL24):​c.367T>C​(p.Tyr123His) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL24 NM_017644.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

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.367T>C	p.Tyr123His	missense	Exon 3 of 8	NP_060114.2	Q6TFL4-1
	KLHL24	NM_001349413.1		c.367T>C	p.Tyr123His	missense	Exon 3 of 9	NP_001336342.1
	KLHL24	NM_001349414.1		c.367T>C	p.Tyr123His	missense	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.367T>C	p.Tyr123His	missense	Exon 3 of 8	ENSP00000242810.6	Q6TFL4-1
	KLHL24	ENST00000454652.6	TSL:1	c.367T>C	p.Tyr123His	missense	Exon 4 of 9	ENSP00000395012.1	Q6TFL4-1
	KLHL24	ENST00000943871.1		c.367T>C	p.Tyr123His	missense	Exon 3 of 10	ENSP00000613930.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.90
Sift	Benign	0.034	D
Sift4G	Benign	0.087	T
Polyphen		0.97	D
Vest4		0.92
MutPred		0.75		Loss of methylation at K128 (P = 0.1026)
MVP		0.80
MPC		1.4
ClinPred		0.98	D
GERP RS		5.4
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.87
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr3-183368511;