Variant 12-56417765-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003920.5(TIMELESS):c.3578G>A(p.Gly1193Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,614,092 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 17 hom. )

Consequence

TIMELESS
NM_003920.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.427

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:

TIMELESS (HGNC:):

TIMELESS links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048228204).

BP6

Variant 12-56417765-C-T is Benign according to our data. Variant chr12-56417765-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 708383.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 466 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5 linkuse as main transcript	c.3578G>A	p.Gly1193Glu	missense_variant	29/29	ENST00000553532.6	NP_003911.2	Q9UNS1-1
TIMELESS	NM_001330295.2 linkuse as main transcript	c.3575G>A	p.Gly1192Glu	missense_variant	29/29		NP_001317224.1	Q9UNS1-2
TIMELESS	NR_138471.2 linkuse as main transcript	n.3715G>A		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TIMELESS	ENST00000553532.6 linkuse as main transcript	c.3578G>A	p.Gly1193Glu	missense_variant	29/29	1	NM_003920.5	ENSP00000450607.1	Q9UNS1-1
TIMELESS	ENST00000229201.4 linkuse as main transcript	c.3575G>A	p.Gly1192Glu	missense_variant	29/29	5		ENSP00000229201.4	Q9UNS1-2
TIMELESS	ENST00000557589.1 linkuse as main transcript	n.2146G>A		non_coding_transcript_exon_variant	13/13	2

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

465

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00301

AC:

756

AN:

251470

Hom.:

AF XY:

0.00313

AC XY:

426

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00444

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00371

AC:

5421

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2695

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00302

Gnomad4 ASJ exome

AF:

0.00738

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000893

Gnomad4 FIN exome

AF:

0.00174

Gnomad4 NFE exome

AF:

0.00420

Gnomad4 OTH exome

AF:

0.00341

GnomAD4 genome

AF:

0.00306

AC:

466

AN:

152210

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00453

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00439

Hom.:

Bravo

AF:

0.00311

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00282

AC:

343

EpiCase

AF:

0.00447

EpiControl

AF:

0.00545

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.0

DANN

Benign

0.23

DEOGEN2

Benign

0.049

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.41

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

0.29

N;N

REVEL

Benign

0.12

Sift

Benign

0.50

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.040

B;.

Vest4

0.046

MVP

0.24

MPC

0.15

ClinPred

0.0019

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.075

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over