12-52567045-G-A

Variant names:

Variant summary

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

The NM_175053.4(KRT74):c.1514C>T(p.Ala505Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,598,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A505A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

KRT74
NM_175053.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.769

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=0.008202374).

BP6

Variant 12-52567045-G-A is Benign according to our data. Variant chr12-52567045-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1099347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT74	NM_175053.4 link	c.1514C>T	p.Ala505Val	missense_variant	Exon 9 of 9	ENST00000305620.3	NP_778223.2	Q7RTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT74	ENST00000305620.3 link	c.1514C>T	p.Ala505Val	missense_variant	Exon 9 of 9	1	NM_175053.4	ENSP00000307240.2	Q7RTS7
KRT74	ENST00000549343.5 link	c.1556C>T	p.Ala519Val	missense_variant	Exon 10 of 10	5		ENSP00000447447.1	F8W1S1
KRT74	ENST00000546384.1 link	n.501C>T		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000146

AC:

AN:

240424

Hom.:

AF XY:

0.000138

AC XY:

AN XY:

130002

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00116

Gnomad SAS exome

AF:

0.0000347

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000927

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1446734

Hom.:

Cov.:

AF XY:

0.0000669

AC XY:

AN XY:

717628

show subpopulations

Gnomad4 AFR exome

AF:

0.0000905

Gnomad4 AMR exome

AF:

0.000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000837

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000299

Gnomad4 OTH exome

AF:

0.000218

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 07, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jul 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

1.6

DANN

Benign

0.89

DEOGEN2

Benign

0.0018

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.22

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.17

Sift

Benign

0.25

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.20

.;B

Vest4

0.059

MVP

0.040

MPC

0.064

ClinPred

0.012

GERP RS

-3.6

Varity_R

0.031

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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