17-41583272-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000526.5(KRT14):c.1237G>A(p.Ala413Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,478 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A413P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 64 hom., cov: 31)

Exomes 𝑓: 0.012 ( 290 hom. )

Consequence

KRT14
NM_000526.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 1.07

Publications

23 publications found

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 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

KRT14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000526.5

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.052458495).

BP6

Variant 17-41583272-C-T is Benign according to our data. Variant chr17-41583272-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 66319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41583272-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 66319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5 link	c.1237G>A	p.Ala413Thr	missense_variant	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.1237G>A	p.Ala413Thr	missense_variant	Exon 6 of 8	1	NM_000526.5	ENSP00000167586.6	P02533
KRT14	ENST00000441550.2 link	n.184G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
KRT14	ENST00000476662.1 link	n.687G>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2435

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0593

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0547

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0469

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00806

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0214

AC:

5374

AN:

251222

AF XY:

0.0191

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0633

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.0540

Gnomad FIN exome

AF:

0.0479

Gnomad NFE exome

AF:

0.00790

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0121

AC:

17656

AN:

1461288

Hom.:

290

Cov.:

AF XY:

0.0113

AC XY:

8223

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33458

American (AMR)

AF:

0.0655

AC:

2929

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26134

East Asian (EAS)

AF:

0.0455

AC:

1807

AN:

39700

South Asian (SAS)

AF:

0.00422

AC:

364

AN:

86236

European-Finnish (FIN)

AF:

0.0453

AC:

2421

AN:

53418

Middle Eastern (MID)

AF:

0.00207

AC:

AN:

5308

European-Non Finnish (NFE)

AF:

0.00832

AC:

9249

AN:

1111974

Other (OTH)

AF:

0.0129

AC:

776

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1094

2188

3283

4377

5471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

410

820

1230

1640

2050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0160

AC:

2438

AN:

152190

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

1398

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00306

AC:

127

AN:

41532

American (AMR)

AF:

0.0594

AC:

908

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.0548

AC:

283

AN:

5160

South Asian (SAS)

AF:

0.00684

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0469

AC:

497

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00806

AC:

548

AN:

67996

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

244

366

488

610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00809

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.0184

AC:

2228

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.00720

EpiControl

AF:

0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17034543, 20180888, 21593775, 21844930, 22832485, 12101866, 25017986, 26929861, 28561874, 28777847, 29784039, 32484238, 32884918) -

KRT14-related disorder

Benign:1

Feb 26, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epidermolysis bullosa simplex 1A, generalized severe;C0080333:Epidermolysis bullosa simplex 1C, localized;C0343111:Naegeli-Franceschetti-Jadassohn syndrome;C0406778:Dermatopathia pigmentosa reticularis;C3715082:Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive;C5561924:Epidermolysis bullosa simplex, Koebner type

Benign:1

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.51

MetaRNN

Benign

0.052

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.3

PhyloP100

1.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.65

Sift

Benign

0.099

Sift4G

Benign

0.18

Polyphen

0.85

Vest4

0.26

MPC

0.73

ClinPred

0.044

GERP RS

5.7

Varity_R

0.32

gMVP

0.88

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over