Variant rs774027 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003920.5(TIMELESS):c.1363A>T(p.Ile455Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,532 control chromosomes in the GnomAD database, including 172,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.42 ( 14833 hom., cov: 31)

Exomes 𝑓: 0.46 ( 157236 hom. )

Consequence

TIMELESS
NM_003920.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.566

Variant links:

Genes affected

TIMELESS (HGNC:11813): (timeless circadian regulator) The protein encoded by this gene is highly conserved and is involved in cell survival after damage or stress, increase in DNA polymerase epsilon activity, maintenance of telomere length, and epithelial cell morphogenesis. The encoded protein also plays a role in the circadian rhythm autoregulatory loop, interacting with the PERIOD genes (PER1, PER2, and PER3) and others to downregulate activation of PER1 by CLOCK/ARNTL. Changes in this gene or its expression may promote prostate cancer, lung cancer, breast cancer, and mental disorders. [provided by RefSeq, Feb 2014]

TIMELESS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.541583E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TIMELESS	NM_003920.5 linkuse as main transcript	c.1363A>T	p.Ile455Leu	missense_variant	12/29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2 linkuse as main transcript	c.1360A>T	p.Ile454Leu	missense_variant	12/29		NP_001317224.1
TIMELESS	NR_138471.2 linkuse as main transcript	n.1541A>T		non_coding_transcript_exon_variant	12/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6 linkuse as main transcript	c.1363A>T	p.Ile455Leu	missense_variant	12/29	1	NM_003920.5	ENSP00000450607	P4	Q9UNS1-1
TIMELESS	ENST00000229201.4 linkuse as main transcript	c.1360A>T	p.Ile454Leu	missense_variant	12/29	5		ENSP00000229201	A2	Q9UNS1-2

Frequencies

GnomAD3 genomes

AF:

0.423

AC:

64203

AN:

151874

Hom.:

14825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.266

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.531

Gnomad EAS

AF:

0.734

Gnomad SAS

AF:

0.503

Gnomad FIN

AF:

0.407

Gnomad MID

AF:

0.528

Gnomad NFE

AF:

0.448

Gnomad OTH

AF:

0.498

GnomAD3 exomes

AF:

0.505

AC:

126268

AN:

249882

Hom.:

34176

AF XY:

0.500

AC XY:

67559

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.259

Gnomad AMR exome

AF:

0.714

Gnomad ASJ exome

AF:

0.523

Gnomad EAS exome

AF:

0.748

Gnomad SAS exome

AF:

0.499

Gnomad FIN exome

AF:

0.416

Gnomad NFE exome

AF:

0.454

Gnomad OTH exome

AF:

0.505

GnomAD4 exome

AF:

0.457

AC:

668422

AN:

1461540

Hom.:

157236

Cov.:

AF XY:

0.458

AC XY:

333156

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.255

Gnomad4 AMR exome

AF:

0.701

Gnomad4 ASJ exome

AF:

0.527

Gnomad4 EAS exome

AF:

0.673

Gnomad4 SAS exome

AF:

0.499

Gnomad4 FIN exome

AF:

0.423

Gnomad4 NFE exome

AF:

0.441

Gnomad4 OTH exome

AF:

0.474

GnomAD4 genome

AF:

0.423

AC:

64231

AN:

151992

Hom.:

14833

Cov.:

AF XY:

0.426

AC XY:

31647

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.267

Gnomad4 AMR

AF:

0.581

Gnomad4 ASJ

AF:

0.531

Gnomad4 EAS

AF:

0.733

Gnomad4 SAS

AF:

0.503

Gnomad4 FIN

AF:

0.407

Gnomad4 NFE

AF:

0.448

Gnomad4 OTH

AF:

0.494

Alfa

AF:

0.453

Hom.:

5476

Bravo

AF:

0.438

TwinsUK

AF:

0.418

AC:

1549

ALSPAC

AF:

0.441

AC:

1701

ESP6500AA

AF:

0.270

AC:

1188

ESP6500EA

AF:

0.454

AC:

3907

ExAC

AF:

0.493

AC:

59829

Asia WGS

AF:

0.570

AC:

1985

AN:

3478

EpiCase

AF:

0.458

EpiControl

AF:

0.467

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.5

DANN

Benign

0.42

DEOGEN2

Benign

0.043

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.32

T;T

MetaRNN

Benign

8.5e-7

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

0.73

N;N

REVEL

Benign

0.016

Sift

Benign

0.53

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0

B;B

Vest4

0.077

MutPred

0.33

Gain of catalytic residue at M453 (P = 0.0075);.;

MPC

0.11

ClinPred

0.000015

GERP RS

-2.3

Varity_R

0.033

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over