12-52367173-C-T

Position:

chr12-52367173-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000257901.7(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. 12/20 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
ENST00000257901.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.495

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 6836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52367173-C-T is described in Lovd as [Benign]. Variant chr12-52367173-C-T is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
KRT85	NM_002283.4 linkuse as main transcript	c.233G>A	p.Arg78His	missense_variant	1/9	ENST00000257901.7	NP_002274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT85	ENST00000257901.7 linkuse as main transcript	c.233G>A	p.Arg78His	missense_variant	1/9	1	NM_002283.4	ENSP00000257901	P1

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

GnomAD3 exomes

AF:

0.0380

AC:

9527

AN:

250428

Hom.:

233

AF XY:

0.0409

AC XY:

5551

AN XY:

135580

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 SAS exome

AF:

0.0665

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

Gnomad4 AFR exome

AF:

0.0268

Gnomad4 AMR exome

AF:

0.0224

Gnomad4 ASJ exome

AF:

0.0576

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0666

Gnomad4 FIN exome

AF:

0.0261

Gnomad4 NFE exome

AF:

0.0465

Gnomad4 OTH exome

AF:

0.0453

GnomAD4 genome

AF:

0.0370

AC:

5637

AN:

152348

Hom.:

128

Cov.:

AF XY:

0.0370

AC XY:

2759

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0246

Gnomad4 AMR

AF:

0.0353

Gnomad4 ASJ

AF:

0.0576

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0669

Gnomad4 FIN

AF:

0.0290

Gnomad4 NFE

AF:

0.0456

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0380

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	This variant is associated with the following publications: (PMID: 27884173, 16525032, 25333069, 22995991) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Ectodermal dysplasia 4, hair/nail type

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2010	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

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

MutationTaster

Benign

0.000060

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

Varity_R

0.061

gMVP

0.64

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over