17-41586461-C-T

Position:

• chr17-41586461-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000526.5(KRT14):​c.374G>A​(p.Arg125His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R125G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 6.11

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 18 ACMG points.

• PM1: In a region_of_interest Coil 1A (size 35) in uniprot entity K1C14_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-41586461-C-T is Pathogenic according to our data. Variant chr17-41586461-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41586461-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT14	NM_000526.5	c.374G>A	p.Arg125His	missense_variant	1/8	ENST00000167586.7	NP_000517.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT14	ENST00000167586.7	c.374G>A	p.Arg125His	missense_variant	1/8	1	NM_000526.5	ENSP00000167586.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2022	Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27882080, 29242947, 29410318, 29784039, 29687370, 1717157, 26432462, 28561874, 28830826, 26707537, 32484238, 33274474, 21176769, 31001817, 16098032, 19854623, 7561171) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 125 of the KRT14 protein (p.Arg125His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant epidermolysis bullosa simplex (PMID: 1717157, 16098032). ClinVar contains an entry for this variant (Variation ID: 14613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT14 protein function. Experimental studies have shown that this missense change affects KRT14 function (PMID: 1717157). This variant disrupts the p.Arg125 amino acid residue in KRT14. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1717157, 16098032). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa simplex 1A, generalized severe Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2000	- -

Dermatopathia pigmentosa reticularis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 07, 2022

ACMG classification criteria: PS4 strong, PM1, PM2 moderated, PM6 moderated, PP3 supporting -

KRT14-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2024

The KRT14 c.374G>A variant is predicted to result in the amino acid substitution p.Arg125His. This variant has been previously reported in the heterozygous state in many individuals with epidermolysis bullosa (see for example Coulombe et al. 1991. PubMed ID: 1717157; Pfendner et al. 2005. PubMed ID: 16098032; Vahidnezhad et al. 2017. PubMed ID: 28830826, Supplementary Table S1; Mariath et al. 2019. PubMed ID: 31001817; Chen et al. 2020. PubMed ID: 32484238). The p125 residue represents a mutation hotspot with alternate amino acids changes (p.Arg125Ser, p.Arg125Gly, p.Arg125Cys, p.Arg125Pro, and p.Arg125Leu) frequently found in individuals with epidermolysis bullosa (https://www.hgmd.cf.ac.uk/ac/index.php). The p.Arg125His variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Loss of stability (P = 0.0774);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.86
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: rs58330629; hg19: chr17-39742713;