Variant chr12-52430579-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004693.3(KRT75):c.997C>T(p.Arg333Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,614,112 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 5 hom. )

Consequence

KRT75
NM_004693.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.05

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 made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.078255296).

BP6

Variant 12-52430579-G-A is Benign according to our data. Variant chr12-52430579-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3049320.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 277 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT75	NM_004693.3 linkuse as main transcript	c.997C>T	p.Arg333Cys	missense_variant	5/9	ENST00000252245.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT75	ENST00000252245.6 linkuse as main transcript	c.997C>T	p.Arg333Cys	missense_variant	5/9	1	NM_004693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

277

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00282

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00191

AC:

481

AN:

251496

Hom.:

AF XY:

0.00177

AC XY:

240

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00292

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00294

AC:

4304

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2049

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00353

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00360

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00182

AC:

277

AN:

152258

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

121

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00282

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00180

AC:

218

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

KRT75-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.77

M_CAP

Benign

0.048

MetaRNN

Benign

0.078

MetaSVM

Uncertain

-0.070

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-6.6

REVEL

Uncertain

0.64

Sift

Uncertain

0.0080

Sift4G

Benign

0.068

Polyphen

1.0

Vest4

0.76

MVP

0.80

MPC

0.54

ClinPred

0.073

GERP RS

4.8

Varity_R

0.31

gMVP

0.57

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