12-52430567-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PS1_ModerateBP4_StrongBP6_ModerateBS2

The NM_004693.3(KRT75):c.1009G>A(p.Glu337Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00984 in 1,614,128 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.0065 ( 5 hom., cov: 33)

Exomes 𝑓: 0.010 ( 104 hom. )

Consequence

KRT75
NM_004693.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.82

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 -8 ACMG points.

PS1

Transcript NM_004693.3 (KRT75) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.019304305).

BP6

Variant 12-52430567-C-T is Benign according to our data. Variant chr12-52430567-C-T is described in ClinVar as [Benign]. Clinvar id is 3037706.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 983 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT75	NM_004693.3 linkuse as main transcript	c.1009G>A	p.Glu337Lys	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.1009G>A	p.Glu337Lys	missense_variant	5/9	1	NM_004693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

983

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00913

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00740

AC:

1860

AN:

251496

Hom.:

AF XY:

0.00794

AC XY:

1079

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00846

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00651

GnomAD4 exome

AF:

0.0102

AC:

14900

AN:

1461832

Hom.:

104

Cov.:

AF XY:

0.0102

AC XY:

7389

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00445

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00886

Gnomad4 FIN exome

AF:

0.00391

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.00848

GnomAD4 genome

AF:

0.00645

AC:

983

AN:

152296

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

467

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00934

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00929

Hom.:

Bravo

AF:

0.00649

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.00760

AC:

923

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00840

EpiControl

AF:

0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

KRT75-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as 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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.92

MVP

0.82

MPC

0.49

ClinPred

0.088

GERP RS

5.7

Varity_R

0.77

gMVP

0.72

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