rs3826550

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000526.5(KRT14):c.280G>A(p.Ala94Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,613,682 control chromosomes in the GnomAD database, including 141,439 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12731 hom., cov: 32)

Exomes 𝑓: 0.41 ( 128708 hom. )

Consequence

KRT14
NM_000526.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.297

Publications

24 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 -19 ACMG points.

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=0.0017464757).

BP6

Variant 17-41586555-C-T is Benign according to our data. Variant chr17-41586555-C-T is described in ClinVar as Benign. ClinVar VariationId is 66336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5 link	c.280G>A	p.Ala94Thr	missense_variant	Exon 1 of 8	ENST00000167586.7	NP_000517.3	P02533

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT14	ENST00000167586.7 link	c.280G>A	p.Ala94Thr	missense_variant	Exon 1 of 8	1	NM_000526.5	ENSP00000167586.6		P02533

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60658

AN:

151884

Hom.:

12729

Cov.:

show subpopulations

Gnomad AFR

AF:

0.439

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.0508

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.338

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.440

Gnomad OTH

AF:

0.421

GnomAD2 exomes

AF:

0.348

AC:

86994

AN:

250158

AF XY:

0.353

show subpopulations

Gnomad AFR exome

AF:

0.432

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.0543

Gnomad FIN exome

AF:

0.330

Gnomad NFE exome

AF:

0.434

Gnomad OTH exome

AF:

0.401

GnomAD4 exome

AF:

0.411

AC:

600059

AN:

1461680

Hom.:

128708

Cov.:

103

AF XY:

0.408

AC XY:

296494

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.435

AC:

14575

AN:

33470

American (AMR)

AF:

0.231

AC:

10307

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.435

AC:

11374

AN:

26136

East Asian (EAS)

AF:

0.0406

AC:

1613

AN:

39698

South Asian (SAS)

AF:

0.284

AC:

24482

AN:

86252

European-Finnish (FIN)

AF:

0.332

AC:

17725

AN:

53326

Middle Eastern (MID)

AF:

0.486

AC:

2801

AN:

5764

European-Non Finnish (NFE)

AF:

0.443

AC:

492566

AN:

1111956

Other (OTH)

AF:

0.408

AC:

24616

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

25536

51073

76609

102146

127682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14672

29344

44016

58688

73360

<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:

0.399

AC:

60691

AN:

152002

Hom.:

12731

Cov.:

AF XY:

0.391

AC XY:

29044

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.439

AC:

18195

AN:

41442

American (AMR)

AF:

0.312

AC:

4770

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.436

AC:

1514

AN:

3470

East Asian (EAS)

AF:

0.0507

AC:

262

AN:

5170

South Asian (SAS)

AF:

0.264

AC:

1269

AN:

4814

European-Finnish (FIN)

AF:

0.338

AC:

3572

AN:

10562

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.440

AC:

29871

AN:

67946

Other (OTH)

AF:

0.417

AC:

881

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1840

3679

5519

7358

9198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.430

Hom.:

6084

Bravo

AF:

0.397

TwinsUK

AF:

0.442

AC:

1639

ALSPAC

AF:

0.445

AC:

1716

ExAC

AF:

0.350

AC:

42413

Asia WGS

AF:

0.168

AC:

586

AN:

3478

EpiCase

AF:

0.453

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 9989794, 25040198, 20128788) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

0.091

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.067

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.13

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

0.30

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.84

REVEL

Uncertain

0.32

Sift

Benign

0.41

Sift4G

Benign

0.18

Polyphen

0.048

Vest4

0.10

MPC

0.46

ClinPred

0.013

GERP RS

5.1

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.083

gMVP

0.81

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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