Variant 17-41583221-GGGCCAAGACTCACTGGGCGTCCTCGCCCTCCAGCAGGCGGCGGTAGGTGGCGATCTCCTGCTCCAGCCGCGTCTTCACGTCCAGCAGGATCTTGTACTCCTGGTTCTGCTGCTCCATCTCGCAGCGGAGCTGGGCCAGCTGCTCCTCCAC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000526.5(KRT14):c.1138_1274+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA(p.Val380fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Consequence

KRT14
NM_000526.5 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

Variant links:

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]

KRT14 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT14	NM_000526.5 link	c.1138_1274+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA	p.Val380fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	6/8	ENST00000167586.7	NP_000517.3	P02533

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRT14	ENST00000167586.7 link	c.1138_1274+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA	p.Val380fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	6/8	1	NM_000526.5	ENSP00000167586.6	P02533
KRT14	ENST00000476662.1 link	n.588_*28delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA		splice_region_variant, non_coding_transcript_exon_variant	4/4	2
KRT14	ENST00000441550.2 link	n.85_221+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	1/2	2
KRT14	ENST00000476662.1 link	n.588_*28delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2024

This variant results in the deletion of part of exon 6 (c.1138_1274+14delinsA) of the KRT14 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in KRT14 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of autosomal dominant epidermolysis bullosa (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.