12-52567100-C-T

Variant names:

Variant summary

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

The NM_175053.4(KRT74):c.1459G>A(p.Ala487Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,603,648 control chromosomes in the GnomAD database, including 2,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 133 hom., cov: 32)

Exomes 𝑓: 0.048 ( 1908 hom. )

Consequence

KRT74
NM_175053.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.440

Publications

11 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=0.0018889904).

BP6

Variant 12-52567100-C-T is Benign according to our data. Variant chr12-52567100-C-T is described in ClinVar as Benign. ClinVar VariationId is 1655951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	NM_175053.4	MANE Select	c.1459G>A	p.Ala487Thr	missense	Exon 9 of 9	NP_778223.2	Q7RTS7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT74	ENST00000305620.3	TSL:1 MANE Select	c.1459G>A	p.Ala487Thr	missense	Exon 9 of 9	ENSP00000307240.2	Q7RTS7
KRT74	ENST00000549343.5	TSL:5	c.1501G>A	p.Ala501Thr	missense	Exon 10 of 10	ENSP00000447447.1	F8W1S1
KRT74	ENST00000546384.1	TSL:4	n.446G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5282

AN:

152048

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.0866

Gnomad AMR

AF:

0.0288

Gnomad ASJ

AF:

0.0484

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00727

Gnomad FIN

AF:

0.0516

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0519

Gnomad OTH

AF:

0.0345

GnomAD2 exomes

AF:

0.0331

AC:

8168

AN:

247088

AF XY:

0.0333

show subpopulations

Gnomad AFR exome

AF:

0.00853

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.0430

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0483

Gnomad NFE exome

AF:

0.0478

Gnomad OTH exome

AF:

0.0446

GnomAD4 exome

AF:

0.0475

AC:

68965

AN:

1451484

Hom.:

1908

Cov.:

AF XY:

0.0463

AC XY:

33337

AN XY:

719846

show subpopulations

African (AFR)

AF:

0.00720

AC:

240

AN:

33316

American (AMR)

AF:

0.0250

AC:

1113

AN:

44440

Ashkenazi Jewish (ASJ)

AF:

0.0446

AC:

1158

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39396

South Asian (SAS)

AF:

0.00753

AC:

645

AN:

85714

European-Finnish (FIN)

AF:

0.0482

AC:

2566

AN:

53206

Middle Eastern (MID)

AF:

0.0278

AC:

159

AN:

5724

European-Non Finnish (NFE)

AF:

0.0546

AC:

60272

AN:

1103960

Other (OTH)

AF:

0.0470

AC:

2812

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3431

6862

10292

13723

17154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2256

4512

6768

9024

11280

<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:

0.0347

AC:

5277

AN:

152164

Hom.:

133

Cov.:

AF XY:

0.0335

AC XY:

2491

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00958

AC:

398

AN:

41526

American (AMR)

AF:

0.0288

AC:

440

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0484

AC:

168

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00707

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0516

AC:

547

AN:

10602

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0518

AC:

3524

AN:

67990

Other (OTH)

AF:

0.0342

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

266

532

797

1063

1329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0431

Hom.:

383

Bravo

AF:

0.0324

TwinsUK

AF:

0.0450

AC:

167

ALSPAC

AF:

0.0540

AC:

208

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.0522

AC:

449

ExAC

AF:

0.0312

AC:

3786

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0557

EpiControl

AF:

0.0529

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.24

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.014

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00049

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

-0.44

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.77

REVEL

Benign

0.18

Sift

Benign

0.63

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.031

MPC

0.063

ClinPred

0.0056

GERP RS

-8.1

Varity_R

0.024

gMVP

0.088

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over