Genetic Variant TIMELESS:p.Val255Val (chr12-56431527-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_003920.5(TIMELESS):c.765G>A(p.Val255Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,506 control chromosomes in the GnomAD database, including 171,672 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.

Frequency

Genomes: 𝑓 0.42 ( 14747 hom., cov: 29)

Exomes 𝑓: 0.46 ( 156925 hom. )

Consequence

TIMELESS
NM_003920.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.480

Publications

31 publications found

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 was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP7

Synonymous conserved (PhyloP=-0.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TIMELESS	NM_003920.5 link	c.765G>A	p.Val255Val	synonymous_variant	Exon 8 of 29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2 link	c.762G>A	p.Val254Val	synonymous_variant	Exon 8 of 29		NP_001317224.1
TIMELESS	NR_138471.2 link	n.943G>A		non_coding_transcript_exon_variant	Exon 8 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6 link	c.765G>A	p.Val255Val	synonymous_variant	Exon 8 of 29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4 link	c.762G>A	p.Val254Val	synonymous_variant	Exon 8 of 29	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes

AF:

0.422

AC:

63965

AN:

151638

Hom.:

14741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.579

Gnomad ASJ

AF:

0.530

Gnomad EAS

AF:

0.728

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.405

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.448

Gnomad OTH

AF:

0.495

GnomAD2 exomes

AF:

0.504

AC:

126334

AN:

250534

AF XY:

0.499

show subpopulations

Gnomad AFR exome

AF:

0.258

Gnomad AMR exome

AF:

0.713

Gnomad ASJ exome

AF:

0.523

Gnomad EAS exome

AF:

0.743

Gnomad FIN exome

AF:

0.416

Gnomad NFE exome

AF:

0.455

Gnomad OTH exome

AF:

0.505

GnomAD4 exome

AF:

0.457

AC:

667604

AN:

1460750

Hom.:

156925

Cov.:

AF XY:

0.458

AC XY:

332749

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.253

AC:

8450

AN:

33434

American (AMR)

AF:

0.699

AC:

31144

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.527

AC:

13747

AN:

26102

East Asian (EAS)

AF:

0.671

AC:

26567

AN:

39622

South Asian (SAS)

AF:

0.496

AC:

42740

AN:

86096

European-Finnish (FIN)

AF:

0.423

AC:

22572

AN:

53364

Middle Eastern (MID)

AF:

0.566

AC:

3262

AN:

5762

European-Non Finnish (NFE)

AF:

0.441

AC:

490632

AN:

1111494

Other (OTH)

AF:

0.472

AC:

28490

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

18830

37661

56491

75322

94152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14926

29852

44778

59704

74630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.422

AC:

63986

AN:

151756

Hom.:

14747

Cov.:

AF XY:

0.425

AC XY:

31495

AN XY:

74146

show subpopulations

African (AFR)

AF:

0.265

AC:

10966

AN:

41388

American (AMR)

AF:

0.580

AC:

8823

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.530

AC:

1838

AN:

3466

East Asian (EAS)

AF:

0.727

AC:

3742

AN:

5148

South Asian (SAS)

AF:

0.499

AC:

2389

AN:

4792

European-Finnish (FIN)

AF:

0.405

AC:

4261

AN:

10522

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.448

AC:

30431

AN:

67926

Other (OTH)

AF:

0.490

AC:

1029

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1710

3420

5129

6839

8549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

596

1192

1788

2384

2980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.459

Hom.:

33672

Bravo

AF:

0.438

Asia WGS

AF:

0.559

AC:

1946

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

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.1

(source)

DANN

Benign

0.61

PhyloP100

-0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over