rs57499817

Positions:

• chr12-52520223-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000424.4(KRT5):​c.74C>T​(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,762 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 3.08

Genes affected

KRT5 (HGNC:6442): (keratin 5) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 12-52520223-G-A is Pathogenic according to our data. Variant chr12-52520223-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52520223-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.74C>T	p.Pro25Leu	missense_variant	1/9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.74C>T	p.Pro25Leu	missense_variant	1/9	1	NM_000424.4	ENSP00000252242	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461762 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727186

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

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	Sep 04, 2020	Published functional studies demonstrate that although P25L does not interfere with alignment and assembly of keratin intermediate filaments, it affects the length and uniformity of the resulting filaments, thus explaining the milder blistering phenotype of EBS-MP (Uttam et al., 1996); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect, although this variant resides within the non-helical variable head domain (V1 region) of keratin 5, which is outside the typical keratin hot spots; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31001817, 30690752, 16581562, 22640275, 21623745, 21375516, 20199538, 20923750, 8799157, 16882168, 16098032, 15827748, 11167681, 10494094, 9129237, 26286811, 15030360, 24964947, 22161089, 23889190, 17229601) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the KRT5 protein (p.Pro25Leu). 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: 8799157, 15030360, 16098032, 16581562, 17229601). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro24Leu. ClinVar contains an entry for this variant (Variation ID: 14648). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KRT5 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa simplex with mottled pigmentation Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2010	- -

KRT5-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

The KRT5 c.74C>T variant is predicted to result in the amino acid substitution p.Pro25Leu. This variant has been reported in individuals with epidermolysis bullosa simplex (EBS) and the affected family members (see for example, Uttam et al. 1996. PubMed ID: 8799157, reported as P24L; Pascucci et al. 2006. PubMed ID: 17229601; Pfendner et al. 2005. PubMed ID: 16098032; Mariath et al. 2019. PubMed ID: 31001817). This variant has also been reported as de novo in an individual with EBS (Table S1, Chen et al. 2023. PubMed ID: 36287101). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Epidermolysis bullosa simplex Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0090
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.60	A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.086	T;T;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.71
MutPred		0.76		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.69
MPC		0.63
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.54

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: rs57499817; hg19: chr12-52914007;