3-183650535-G-T

Variant names:

• chr3-183650535-G-T
• rs1261493748
• NM_017644.3:c.179G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001349428.1(KLHL24):​c.-788G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHL24 NM_001349428.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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.179G>T	p.Arg60Leu	missense	Exon 3 of 8	NP_060114.2	Q6TFL4-1
	KLHL24	NM_001349428.1		c.-788G>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001336357.1
	KLHL24	NM_001349429.1		c.-788G>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.179G>T	p.Arg60Leu	missense	Exon 3 of 8	ENSP00000242810.6	Q6TFL4-1
	KLHL24	ENST00000454652.6	TSL:1	c.179G>T	p.Arg60Leu	missense	Exon 4 of 9	ENSP00000395012.1	Q6TFL4-1
	KLHL24	ENST00000943871.1		c.179G>T	p.Arg60Leu	missense	Exon 3 of 10	ENSP00000613930.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.88		Loss of solvent accessibility (P = 0.1362)
MVP		0.87
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.011	Neutral
Varity_R		0.70
gMVP		0.96
Mutation Taster		=29/71	disease causing

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: rs1261493748; hg19: chr3-183368323;