12-52367173-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_002283.4(KRT85):c.233G>A(p.Arg78His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,613,746 control chromosomes in the GnomAD database, including 1,784 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 128 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1656 hom. )

Consequence

KRT85
NM_002283.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6O:1

Conservation

PhyloP100: 0.495

Publications

18 publications found

Variant links:

Genes affected

KRT85 (HGNC:6462): (keratin 85) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. [provided by RefSeq, Jul 2008]

KRT85 Gene-Disease associations (from GenCC):

ectodermal dysplasia 4, hair/nail type
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pure hair and nail ectodermal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT85 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=0.020342559).

BP6

Variant 12-52367173-C-T is Benign according to our data. Variant chr12-52367173-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 6836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT85	NM_002283.4 link	c.233G>A	p.Arg78His	missense_variant	Exon 1 of 9	ENST00000257901.7	NP_002274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT85	ENST00000257901.7 link	c.233G>A	p.Arg78His	missense_variant	Exon 1 of 9	1	NM_002283.4	ENSP00000257901.3

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5648

AN:

152230

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0354

Gnomad ASJ

AF:

0.0576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0674

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0456

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0380

AC:

9527

AN:

250428

AF XY:

0.0409

show subpopulations

Gnomad AFR exome

AF:

0.0237

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0550

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.0440

Gnomad OTH exome

AF:

0.0430

GnomAD4 exome

AF:

0.0447

AC:

65278

AN:

1461398

Hom.:

1656

Cov.:

AF XY:

0.0455

AC XY:

33075

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.0268

AC:

898

AN:

33462

American (AMR)

AF:

0.0224

AC:

1000

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

1503

AN:

26116

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.0666

AC:

5739

AN:

86228

European-Finnish (FIN)

AF:

0.0261

AC:

1394

AN:

53400

Middle Eastern (MID)

AF:

0.0544

AC:

296

AN:

5444

European-Non Finnish (NFE)

AF:

0.0465

AC:

51712

AN:

1111996

Other (OTH)

AF:

0.0453

AC:

2732

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

4991

9982

14973

19964

24955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1994

3988

5982

7976

9970

<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:

0.0370

AC:

5637

AN:

152348

Hom.:

128

Cov.:

AF XY:

0.0370

AC XY:

2759

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0246

AC:

1023

AN:

41584

American (AMR)

AF:

0.0353

AC:

541

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

200

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0669

AC:

323

AN:

4830

European-Finnish (FIN)

AF:

0.0290

AC:

308

AN:

10620

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0456

AC:

3105

AN:

68030

Other (OTH)

AF:

0.0336

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

281

562

842

1123

1404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0394

Hom.:

127

Bravo

AF:

0.0354

TwinsUK

AF:

0.0504

AC:

187

ALSPAC

AF:

0.0496

AC:

191

ESP6500AA

AF:

0.0267

AC:

117

ESP6500EA

AF:

0.0485

AC:

416

ExAC

AF:

0.0372

AC:

4517

Asia WGS

AF:

0.0370

AC:

129

AN:

3478

EpiCase

AF:

0.0470

EpiControl

AF:

0.0488

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 16, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 16525032, 25333069, 22995991) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Ectodermal dysplasia 4, hair/nail type

Pathogenic:1Benign:2

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of ectodermal dysplasia 4, hair/nail type (MIM#602032), with 114 homozygotes in gnomAD v3. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 533/12976=4.1% -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.21

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

PhyloP100

0.49

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.4

REVEL

Benign

0.27

Sift

Benign

0.53

Sift4G

Benign

0.55

Polyphen

0.20

Vest4

0.12

MPC

1.2

ClinPred

0.0037

GERP RS

3.3

PromoterAI

-0.0044

Neutral

(source)

Varity_R

0.061

gMVP

0.64

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over