chr17-41583221-GGGCCAAGACTCACTGGGCGTCCTCGCCCTCCAGCAGGCGGCGGTAGGTGGCGATCTCCTGCTCCAGCCGCGTCTTCACGTCCAGCAGGATCTTGTACTCCTGGTTCTGCTGCTCCATCTCGCAGCGGAGCTGGGCCAGCTGCTCCTCCAC-T

Variant names:

• chr17-41583221-GGGCCAAGACTCACTGGGCGTCCTCGCCCTCCAGCAGGCGGCGGTAGGTGGCGATCTCCTGCTCCAGCCGCGTCTTCACGTCCAGCAGGATCTTGTACTCCTGGTTCTGCTGCTCCATCTCGCAGCGGAGCTGGGCCAGCTGCTCCTCCAC-T
• NM_000526.5:c.1138_1274+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex 1A, generalized severe

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet
• Naegeli-Franceschetti-Jadassohn syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• dermatopathia pigmentosa reticularis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• epidermolysis bullosa simplex 1B, generalized intermediate

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 1C, localized

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000526.5. 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
	KRT14	NM_000526.5	MANE Select	c.1138_1274+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA	p.Val380fs	frameshift splice_donor splice_region intron	Exon 6 of 8	NP_000517.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT14	ENST00000167586.7	TSL:1 MANE Select	c.1138_1274+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA	p.Val380fs	frameshift splice_donor splice_region intron	Exon 6 of 8	ENSP00000167586.6	P02533
	KRT14	ENST00000476662.1	TSL:2	n.588_*28delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA		splice_region non_coding_transcript_exon	Exon 4 of 4
	KRT14	ENST00000441550.2	TSL:2	n.85_221+14delGTGGAGGAGCAGCTGGCCCAGCTCCGCTGCGAGATGGAGCAGCAGAACCAGGAGTACAAGATCCTGCTGGACGTGAAGACGCGGCTGGAGCAGGAGATCGCCACCTACCGCCGCCTGCTGGAGGGCGAGGACGCCCAGTGAGTCTTGGCCCinsA		splice_donor splice_region intron non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

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

Other links and lift over

hg19: chr17-39739473;