rs2279665

chr12-56433910-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_003920.5(TIMELESS):c.114G>C(p.Leu38=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,613,744 control chromosomes in the GnomAD database, including 240,724 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 0.55 (23885 hom., cov: 32)
  • Exomes 𝑓: 0.54 (216839 hom.)
• Consequence: TIMELESS NM_003920.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP7: Synonymous conserved (PhyloP=2.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.114G>C	p.Leu38=	synonymous_variant	3/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.114G>C	p.Leu38=	synonymous_variant	3/29
TIMELESS	NR_138471.2	n.292G>C		non_coding_transcript_exon_variant	3/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.114G>C	p.Leu38=	synonymous_variant	3/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.114G>C	p.Leu38=	synonymous_variant	3/29	5		A2

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83722 AN: 151932 Hom.: 23838 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.489

GnomAD3 exomes AF: 0.488 AC: 122516 AN: 250990 Hom.: 31859 AF XY: 0.495 AC XY: 67169 AN XY: 135656

Gnomad AFR exome AF: 0.644

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.502

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.540 AC: 789104 AN: 1461694 Hom.: 216839 Cov.: 60 AF XY: 0.539 AC XY: 392209 AN XY: 727126

Gnomad4 AFR exome AF: 0.643

Gnomad4 AMR exome AF: 0.296

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.329

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.522

GnomAD4 genome AF: 0.551 AC: 83826 AN: 152050 Hom.: 23885 Cov.: 32 AF XY: 0.549 AC XY: 40823 AN XY: 74326

Gnomad4 AFR AF: 0.641

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.273

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.495

Alfa AF: 0.539 Hom.: 7159

Bravo AF: 0.533

Asia WGS AF: 0.436 AC: 1514 AN: 3478

EpiCase AF: 0.542

EpiControl AF: 0.532

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	11
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2279665; hg19: chr12-56827694; COSMIC: COSV57509960;