chr17-41583872-A-G

Position:

• chr17-41583872-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000526.5(KRT14):​c.815T>C​(p.Met272Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.51

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_000526.5 (KRT14) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest Linker 12 (size 22) in uniprot entity K1C14_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000526.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 17-41583872-A-G is Pathogenic according to our data. Variant chr17-41583872-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT14	NM_000526.5	c.815T>C	p.Met272Thr	missense_variant	4/8	ENST00000167586.7	NP_000517.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT14	ENST00000167586.7	c.815T>C	p.Met272Thr	missense_variant	4/8	1	NM_000526.5	ENSP00000167586.6
KRT14	ENST00000476662.1	n.265T>C		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	KRT14: PM1, PM2, PM5, PP1:Moderate, PS4:Moderate -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2016	The M272T pathogenic variant in the KRT14 gene has been reported previously in association with EBS. It is found in the linker L12 region where variants usually result in milder forms of EBS. The M272T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M272T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue ( M272R) and in nearby residues (V268D, V270M,A, V273G, D273G, A274D) have been reported in the Human Gene Mutation Database in association with EBS (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret M272T as a pathogenic variant. -

Epidermolysis bullosa simplex Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 05, 2023

This sequence change in KRT14 is predicted to replace methionine with threonine at codon 272, p.(Met272Thr). The methionine residue is moderately conserved (100 vertebrates, UCSC), and is located in the L12 rod domain. There is a moderate physicochemical difference between methionine and threonine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least seven probands with an immunohistochemical diagnosis of epidermolysis bullosa simplex (EBS) and as a de novo occurrence with unconfirmed parental relationships in one individual with EBS (PMID: 16786515, 20199538, 26432462, 29242947). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.877). Another missense variant c.815T>G, p.(Met272Arg) in the same codon with similar physicochemical properties to the variant under assessment has been classified as likely pathogenic for EBS (PMID: 7682883, 21375516). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM5, PM6, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.62	P
Vest4		0.61
MutPred		0.82		Loss of stability (P = 0.0272);
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.45

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: rs61371557; hg19: chr17-39740124;