12-52433824-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BA1

The NM_004693.3(KRT75):c.481G>A(p.Ala161Thr) variant causes a missense change. The variant allele was found at a frequency of 0.114 in 1,613,898 control chromosomes in the GnomAD database, including 11,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. A161A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 1633 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9627 hom. )

Consequence

KRT75
NM_004693.3 missense

Scores

Clinical Significance

Benign; risk factor no assertion criteria provided B:1O:2

Conservation

PhyloP100: 5.03

Publications

33 publications found

Variant links:

Genes affected

KRT75 (HGNC:24431): (keratin 75) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. This gene is expressed in the companion layer, upper germinative matrix region of the hair follicle, and medulla of the hair shaft. The encoded protein plays an essential role in hair and nail formation. Variations in this gene have been associated with the hair disorders pseudofolliculitis barbae (PFB) and loose anagen hair syndrome (LAHS). [provided by RefSeq, Oct 2008]

KRT75 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0026835501).

BP6

Variant 12-52433824-C-T is Benign according to our data. Variant chr12-52433824-C-T is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 1891.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT75	NM_004693.3 link	c.481G>A	p.Ala161Thr	missense_variant	Exon 1 of 9	ENST00000252245.6	NP_004684.2	O95678

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT75	ENST00000252245.6 link	c.481G>A	p.Ala161Thr	missense_variant	Exon 1 of 9	1	NM_004693.3	ENSP00000252245.5		O95678

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21155

AN:

151964

Hom.:

1629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.185

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.0718

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.125

AC:

31496

AN:

251484

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.0684

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.111

AC:

162095

AN:

1461816

Hom.:

9627

Cov.:

AF XY:

0.111

AC XY:

81044

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.191

AC:

6402

AN:

33478

American (AMR)

AF:

0.174

AC:

7770

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

4376

AN:

26134

East Asian (EAS)

AF:

0.0717

AC:

2847

AN:

39700

South Asian (SAS)

AF:

0.133

AC:

11479

AN:

86256

European-Finnish (FIN)

AF:

0.103

AC:

5518

AN:

53420

Middle Eastern (MID)

AF:

0.185

AC:

1068

AN:

5762

European-Non Finnish (NFE)

AF:

0.104

AC:

115328

AN:

1111954

Other (OTH)

AF:

0.121

AC:

7307

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

8871

17742

26612

35483

44354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4304

8608

12912

17216

21520

<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:

0.139

AC:

21180

AN:

152082

Hom.:

1633

Cov.:

AF XY:

0.140

AC XY:

10372

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.185

AC:

7683

AN:

41470

American (AMR)

AF:

0.184

AC:

2810

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

565

AN:

3470

East Asian (EAS)

AF:

0.0718

AC:

371

AN:

5166

South Asian (SAS)

AF:

0.133

AC:

642

AN:

4816

European-Finnish (FIN)

AF:

0.102

AC:

1078

AN:

10596

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.109

AC:

7408

AN:

67970

Other (OTH)

AF:

0.154

AC:

325

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

901

1802

2703

3604

4505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.120

Hom.:

4911

Bravo

AF:

0.146

TwinsUK

AF:

0.0976

AC:

362

ALSPAC

AF:

0.108

AC:

416

ESP6500AA

AF:

0.179

AC:

789

ESP6500EA

AF:

0.111

AC:

958

ExAC

AF:

0.123

AC:

14943

Asia WGS

AF:

0.111

AC:

390

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.120

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KRT75-related disorder

Benign:1

Oct 22, 2019

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). -

Pseudofolliculitis barbae

Other:1

Mar 01, 2004

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

4.3

PhyloP100

5.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.29

MPC

0.47

ClinPred

0.10

GERP RS

5.7

Varity_R

0.85

gMVP

0.86

Mutation Taster

=37/63

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