dbSNP rs11171846: TIMELESS:c.-61-41G>A (chr12-56434272-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003920.5(TIMELESS):c.-61-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0744 in 936,264 control chromosomes in the GnomAD database, including 3,250 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 0.064 ( 427 hom., cov: 32)

Exomes 𝑓: 0.076 ( 2823 hom. )

Consequence

TIMELESS
NM_003920.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.508

Publications

16 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TIMELESS	NM_003920.5 link	c.-61-41G>A	intron_variant	Intron 1 of 28	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2 link	c.-61-41G>A	intron_variant	Intron 1 of 28		NP_001317224.1
TIMELESS	NR_138471.2 link	n.118-41G>A	intron_variant	Intron 1 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6 link	c.-61-41G>A		intron_variant	Intron 1 of 28	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4 link	c.-61-41G>A		intron_variant	Intron 1 of 28	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes

AF:

0.0641

AC:

9753

AN:

152104

Hom.:

428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.0731

Gnomad ASJ

AF:

0.167

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0380

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.0926

Gnomad OTH

AF:

0.0904

GnomAD4 exome

AF:

0.0764

AC:

59929

AN:

784042

Hom.:

2823

Cov.:

AF XY:

0.0757

AC XY:

30990

AN XY:

409506

show subpopulations

African (AFR)

AF:

0.0149

AC:

291

AN:

19592

American (AMR)

AF:

0.0570

AC:

1964

AN:

34476

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

3335

AN:

20680

East Asian (EAS)

AF:

0.000115

AC:

AN:

34784

South Asian (SAS)

AF:

0.0373

AC:

2473

AN:

66338

European-Finnish (FIN)

AF:

0.0583

AC:

2852

AN:

48886

Middle Eastern (MID)

AF:

0.143

AC:

628

AN:

4400

European-Non Finnish (NFE)

AF:

0.0876

AC:

45286

AN:

517084

Other (OTH)

AF:

0.0819

AC:

3096

AN:

37802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2747

5495

8242

10990

13737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<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:

0.0640

AC:

9743

AN:

152222

Hom.:

427

Cov.:

AF XY:

0.0620

AC XY:

4612

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0158

AC:

657

AN:

41548

American (AMR)

AF:

0.0729

AC:

1115

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

580

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5188

South Asian (SAS)

AF:

0.0376

AC:

181

AN:

4816

European-Finnish (FIN)

AF:

0.0575

AC:

609

AN:

10584

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0926

AC:

6298

AN:

68000

Other (OTH)

AF:

0.0890

AC:

188

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

475

950

1424

1899

2374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0861

Hom.:

2910

Bravo

AF:

0.0642

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

4.8

(source)

DANN

Benign

0.73

PhyloP100

0.51

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