Variant 12-52567133-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_175053.4(KRT74):c.1426C>T(p.Pro476Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000881 in 1,605,792 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 6 hom. )

Consequence

KRT74
NM_175053.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.565

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044849813).

BP6

Variant 12-52567133-G-A is Benign according to our data. Variant chr12-52567133-G-A is described in ClinVar as [Benign]. Clinvar id is 729449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT74	NM_175053.4 linkuse as main transcript	c.1426C>T	p.Pro476Ser	missense_variant	9/9	ENST00000305620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KRT74	ENST00000305620.3 linkuse as main transcript	c.1426C>T	p.Pro476Ser	missense_variant	9/9	1	NM_175053.4	P1
KRT74	ENST00000549343.5 linkuse as main transcript	c.1468C>T	p.Pro490Ser	missense_variant	10/10	5
KRT74	ENST00000546384.1 linkuse as main transcript	n.413C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

251

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00126

AC:

310

AN:

245588

Hom.:

AF XY:

0.00114

AC XY:

152

AN XY:

133060

show subpopulations

Gnomad AFR exome

AF:

0.00249

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000776

Gnomad OTH exome

AF:

0.00300

GnomAD4 exome

AF:

0.000802

AC:

1166

AN:

1453520

Hom.:

Cov.:

AF XY:

0.000810

AC XY:

584

AN XY:

721428

show subpopulations

Gnomad4 AFR exome

AF:

0.00279

Gnomad4 AMR exome

AF:

0.00200

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000516

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00163

AC:

248

AN:

152272

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000765

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000980

AC:

119

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KRT74-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0070

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.62

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.33

N;N

REVEL

Benign

0.23

Sift

Benign

0.63

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.98

.;D

Vest4

0.21

MVP

0.45

MPC

0.087

ClinPred

0.018

GERP RS

0.23

Varity_R

0.038

gMVP

0.18

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