rs58380626

Positions:

• chr17-41583266-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000526.5(KRT14):​c.1243T>C​(p.Tyr415His) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y415C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.32

Genes affected

KRT14 (HGNC:6416): (keratin 14) This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000526.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-41583265-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 66322.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-41583266-A-G is Pathogenic according to our data. Variant chr17-41583266-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14621.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT14	NM_000526.5	c.1243T>C	p.Tyr415His	missense_variant	6/8	ENST00000167586.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT14	ENST00000167586.7	c.1243T>C	p.Tyr415His	missense_variant	6/8	1	NM_000526.5	P1
KRT14	ENST00000441550.2	n.190T>C		non_coding_transcript_exon_variant	1/2	2
KRT14	ENST00000476662.1	n.693T>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2015	The Y415H missense variant in the KRT14 gene has been reported previously in two patients withEpidermolysis Bullosa Simplex (EBS), one with a milder form of the disorder and one with severe generalizedblistering (Hut et al., 2000; Rugg et al., 2000). Y415H was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. This substitution is located at a highly conserved position in thehelix termination motif of the KRT14 gene where a tyrosine residue is also present in other filament proteins(Rugg et al., 2000). We interpret Y415H as a pathogenic variant. -

Epidermolysis bullosa simplex, Koebner type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.96		Loss of phosphorylation at Y415 (P = 0.0467);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs58380626; hg19: chr17-39739518;