12-56418000-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003920.5(TIMELESS):c.3463G>A(p.Ala1155Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1155D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

TIMELESS
NM_003920.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.591

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007472396).

BP6

Variant 12-56418000-C-T is Benign according to our data. Variant chr12-56418000-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2470126.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 103 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003920.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMELESS	NM_003920.5	MANE Select	c.3463G>A	p.Ala1155Thr	missense	Exon 28 of 29	NP_003911.2	Q9UNS1-1
TIMELESS	NM_001330295.2		c.3460G>A	p.Ala1154Thr	missense	Exon 28 of 29	NP_001317224.1	Q9UNS1-2
TIMELESS	NR_138471.2		n.3600G>A		non_coding_transcript_exon	Exon 28 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.3463G>A	p.Ala1155Thr	missense	Exon 28 of 29	ENSP00000450607.1	Q9UNS1-1
TIMELESS	ENST00000865172.1		c.3484G>A	p.Ala1162Thr	missense	Exon 28 of 29	ENSP00000535231.1
TIMELESS	ENST00000927926.1		c.3484G>A	p.Ala1162Thr	missense	Exon 28 of 29	ENSP00000597985.1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251468

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112012

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000676

AC:

103

AN:

152308

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

41554

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000194

Hom.:

Bravo

AF:

0.000593

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.16

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.030

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.32

M_CAP

Benign

0.0016

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.28

PhyloP100

-0.59

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.11

REVEL

Benign

0.0070

Sift

Benign

0.61

Sift4G

Benign

0.71

Polyphen

0.0030

Vest4

0.075

MVP

0.21

MPC

0.11

ClinPred

0.0031

GERP RS

-4.8

Varity_R

0.015

gMVP

0.069

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over