dbSNP rs2291739: TIMELESS:p.Pro1018Leu (chr12-56420869-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_003920.5(TIMELESS):c.3053C>T(p.Pro1018Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,613,674 control chromosomes in the GnomAD database, including 240,361 homozygotes. In-silico tool predicts 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.48 ( 18702 hom., cov: 31)

Exomes 𝑓: 0.55 ( 221659 hom. )

Consequence

TIMELESS
NM_003920.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.26

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026855469).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5 link	c.3053C>T	p.Pro1018Leu	missense_variant	Exon 25 of 29	ENST00000553532.6	NP_003911.2	Q9UNS1-1
TIMELESS	NM_001330295.2 link	c.3050C>T	p.Pro1017Leu	missense_variant	Exon 25 of 29		NP_001317224.1	Q9UNS1-2
TIMELESS	NR_138471.2 link	n.3190C>T		non_coding_transcript_exon_variant	Exon 25 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TIMELESS	ENST00000553532.6 link	c.3053C>T	p.Pro1018Leu	missense_variant	Exon 25 of 29	1	NM_003920.5	ENSP00000450607.1	Q9UNS1-1
TIMELESS	ENST00000229201.4 link	c.3050C>T	p.Pro1017Leu	missense_variant	Exon 25 of 29	5		ENSP00000229201.4	Q9UNS1-2
TIMELESS	ENST00000553314.1 link	n.141C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3
TIMELESS	ENST00000557589.1 link	n.1621C>T		non_coding_transcript_exon_variant	Exon 9 of 13	2

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73273

AN:

151840

Hom.:

18693

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.432

Gnomad ASJ

AF:

0.472

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.489

Gnomad FIN

AF:

0.632

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.563

Gnomad OTH

AF:

0.454

GnomAD3 exomes

AF:

0.491

AC:

123363

AN:

251054

Hom.:

31813

AF XY:

0.501

AC XY:

67940

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.346

Gnomad AMR exome

AF:

0.369

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.289

Gnomad SAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.622

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.510

GnomAD4 exome

AF:

0.546

AC:

798009

AN:

1461716

Hom.:

221659

Cov.:

AF XY:

0.546

AC XY:

396746

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.341

Gnomad4 AMR exome

AF:

0.374

Gnomad4 ASJ exome

AF:

0.480

Gnomad4 EAS exome

AF:

0.363

Gnomad4 SAS exome

AF:

0.498

Gnomad4 FIN exome

AF:

0.614

Gnomad4 NFE exome

AF:

0.570

Gnomad4 OTH exome

AF:

0.517

GnomAD4 genome

AF:

0.482

AC:

73309

AN:

151958

Hom.:

18702

Cov.:

AF XY:

0.485

AC XY:

36037

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.352

Gnomad4 AMR

AF:

0.432

Gnomad4 ASJ

AF:

0.472

Gnomad4 EAS

AF:

0.297

Gnomad4 SAS

AF:

0.490

Gnomad4 FIN

AF:

0.632

Gnomad4 NFE

AF:

0.563

Gnomad4 OTH

AF:

0.456

Alfa

AF:

0.522

Hom.:

32849

Bravo

AF:

0.455

TwinsUK

AF:

0.595

AC:

2205

ALSPAC

AF:

0.570

AC:

2198

ESP6500AA

AF:

0.354

AC:

1561

ESP6500EA

AF:

0.557

AC:

4786

ExAC

AF:

0.492

AC:

59757

Asia WGS

AF:

0.408

AC:

1418

AN:

3478

EpiCase

AF:

0.551

EpiControl

AF:

0.541

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;.

Vest4

0.50

MPC

0.55

ClinPred

0.027

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.69

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over