Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000305620.3(KRT74):c.495C>G(p.Asn165Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,613,830 control chromosomes in the GnomAD database, including 4,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 411 hom., cov: 32)

Exomes 𝑓: 0.063 ( 4349 hom. )

Consequence

KRT74
ENST00000305620.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.08

Publications

20 publications found

Variant links:

Genes affected

KRT74 (HGNC:28929): (keratin 74) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This protein belongs to a family of keratins that are specifically expressed in the inner root sheath of hair follicles.[provided by RefSeq, Jun 2009]

KRT74 Gene-Disease associations (from GenCC):

autosomal dominant wooly hair
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypotrichosis 3
Inheritance: AD Classification: MODERATE Submitted by: G2P
hypotrichosis simplex of the scalp
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated familial wooly hair disorder
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pure hair and nail ectodermal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT74 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017719865).

BP6

Variant 12-52572644-G-C is Benign according to our data. Variant chr12-52572644-G-C is described in ClinVar as Benign. ClinVar VariationId is 1289755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000305620.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	NM_175053.4	MANE Select	c.495C>G	p.Asn165Lys	missense	Exon 2 of 9	NP_778223.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	ENST00000305620.3	TSL:1 MANE Select	c.495C>G	p.Asn165Lys	missense	Exon 2 of 9	ENSP00000307240.2
	KRT74	ENST00000549343.5	TSL:5	c.495C>G	p.Asn165Lys	missense	Exon 2 of 10	ENSP00000447447.1

Frequencies

GnomAD3 genomes

AF:

0.0501

AC:

7625

AN:

152124

Hom.:

411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0844

Gnomad EAS

AF:

0.306

Gnomad SAS

AF:

0.0806

Gnomad FIN

AF:

0.0398

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0562

Gnomad OTH

AF:

0.0526

GnomAD2 exomes

AF:

0.0698

AC:

17561

AN:

251432

AF XY:

0.0716

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.0355

Gnomad ASJ exome

AF:

0.0820

Gnomad EAS exome

AF:

0.303

Gnomad FIN exome

AF:

0.0408

Gnomad NFE exome

AF:

0.0543

Gnomad OTH exome

AF:

0.0585

GnomAD4 exome

AF:

0.0631

AC:

92269

AN:

1461588

Hom.:

4349

Cov.:

AF XY:

0.0638

AC XY:

46392

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00825

AC:

276

AN:

33472

American (AMR)

AF:

0.0344

AC:

1537

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0835

AC:

2181

AN:

26130

East Asian (EAS)

AF:

0.300

AC:

11890

AN:

39692

South Asian (SAS)

AF:

0.0774

AC:

6675

AN:

86246

European-Finnish (FIN)

AF:

0.0409

AC:

2185

AN:

53420

Middle Eastern (MID)

AF:

0.0473

AC:

273

AN:

5766

European-Non Finnish (NFE)

AF:

0.0568

AC:

63110

AN:

1111752

Other (OTH)

AF:

0.0686

AC:

4142

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

4560

9119

13679

18238

22798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2492

4984

7476

9968

12460

<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:

0.0500

AC:

7619

AN:

152242

Hom.:

411

Cov.:

AF XY:

0.0508

AC XY:

3785

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0110

AC:

456

AN:

41554

American (AMR)

AF:

0.0306

AC:

468

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0844

AC:

293

AN:

3472

East Asian (EAS)

AF:

0.306

AC:

1582

AN:

5172

South Asian (SAS)

AF:

0.0800

AC:

386

AN:

4822

European-Finnish (FIN)

AF:

0.0398

AC:

422

AN:

10604

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0562

AC:

3819

AN:

68006

Other (OTH)

AF:

0.0554

AC:

117

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

357

714

1071

1428

1785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0636

Hom.:

367

Bravo

AF:

0.0476

TwinsUK

AF:

0.0607

AC:

225

ALSPAC

AF:

0.0589

AC:

227

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0549

AC:

472

ExAC

AF:

0.0693

AC:

8409

Asia WGS

AF:

0.144

AC:

500

AN:

3478

EpiCase

AF:

0.0540

EpiControl

AF:

0.0557

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.9

MutationAssessor

Pathogenic

4.0

PhyloP100

3.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.35

MutPred

0.43

Gain of ubiquitination at N165 (P = 0.0258)

MPC

0.42

ClinPred

0.067

GERP RS

3.8

Varity_R

0.91

gMVP

0.76

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over