17-41583872-A-G

Variant names:

• chr17-41583872-A-G
• rs61371557
• NM_000526.5:c.815T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M272R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.51
• Publications: 9 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: Orphanet, Ambry Genetics, Genomics England PanelApp
• Naegeli-Franceschetti-Jadassohn syndrome

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr17-41583872-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14617.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.8353 (below the threshold of 3.09). Trascript score misZ: 1.2925 (below the threshold of 3.09). GenCC associations: The gene is linked to epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive, Naegeli-Franceschetti-Jadassohn syndrome, dermatopathia pigmentosa reticularis, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 2F, with mottled pigmentation, epidermolysis bullosa simplex 1C, localized, epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex.
• 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 VariationId is 66378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5	c.815T>C	p.Met272Thr	missense_variant	Exon 4 of 8	ENST00000167586.7	NP_000517.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

May 10, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 17039244, 16156024, 29242947, 36430820, 24024749, 26432462, 20199538, 16786515) -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KRT14: PM1, PM2, PM5, PP1:Moderate, PS4:Moderate -

Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive Pathogenic:1

Mar 24, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM5_STR,PS4_MOD,PM2,PM1_SUP,PP3 -

Epidermolysis bullosa simplex Pathogenic:1

May 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.5
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
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61371557; hg19: chr17-39740124;