dbSNP rs56974573: KRT14:p.Glu375del (chr17-41583383-TCTC-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate

The NM_000526.5(KRT14):c.1123_1125delGAG(p.Glu375del) variant causes a conservative inframe deletion 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

KRT14
NM_000526.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 1.37

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a region_of_interest Coil 2 (size 138) in uniprot entity K1C14_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000526.5

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000526.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 17-41583383-TCTC-T is Pathogenic according to our data. Variant chr17-41583383-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66301.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-41583383-TCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5 link	c.1123_1125delGAG	p.Glu375del	conservative_inframe_deletion	Exon 6 of 8	ENST00000167586.7	NP_000517.3	P02533

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT14	ENST00000167586.7 link	c.1123_1125delGAG	p.Glu375del	conservative_inframe_deletion	Exon 6 of 8	1	NM_000526.5	ENSP00000167586.6	P02533
KRT14	ENST00000441550.2 link	n.70_72delGAG		non_coding_transcript_exon_variant	Exon 1 of 2	2
KRT14	ENST00000476662.1 link	n.573_575delGAG		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

Dec 30, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acids in a non-repeat region; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33274474, 7506606, 10733662, 16786515, 28561874) -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Epidermolysis bullosa simplex 1C, localized

Pathogenic:1

Nov 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing