rs2291739

chr12-56420869-G-Achr12-56420869-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (18702 hom., cov: 31)
  • Exomes 𝑓: 0.55 (221659 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.26

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]

ACMG classification

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/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.3053C>T	p.Pro1018Leu	missense_variant	25/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.3050C>T	p.Pro1017Leu	missense_variant	25/29
TIMELESS	NR_138471.2	n.3190C>T		non_coding_transcript_exon_variant	25/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3053C>T	p.Pro1018Leu	missense_variant	25/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.3050C>T	p.Pro1017Leu	missense_variant	25/29	5		A2
TIMELESS	ENST00000553314.1	n.141C>T		non_coding_transcript_exon_variant	2/3	3
TIMELESS	ENST00000557589.1	n.1621C>T		non_coding_transcript_exon_variant	9/13	2

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73273 AN: 151840 Hom.: 18693 Cov.: 31

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

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.: 64 AF XY: 0.546 AC XY: 396746 AN XY: 727166

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.: 31 AF XY: 0.485 AC XY: 36037 AN XY: 74254

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	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	3.5e-11	P;P;P
PrimateAI	Uncertain	0.51	T
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	T
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

Other links and lift over

dbSNP: rs2291739; hg19: chr12-56814653; COSMIC: COSV57514991; COSMIC: COSV57514991;