rs2291739

Variant names:

• chr12-56420869-G-A
• rs2291739
• NM_003920.5:c.3053C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-56420869-G-A
• chr12-56420869-G-C

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 53 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.3053C>T	p.Pro1018Leu	missense_variant	Exon 25 of 29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.3050C>T	p.Pro1017Leu	missense_variant	Exon 25 of 29		NP_001317224.1
TIMELESS	NR_138471.2	n.3190C>T		non_coding_transcript_exon_variant	Exon 25 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3053C>T	p.Pro1018Leu	missense_variant	Exon 25 of 29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.3050C>T	p.Pro1017Leu	missense_variant	Exon 25 of 29	5		ENSP00000229201.4
TIMELESS	ENST00000553314.1	n.141C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3
TIMELESS	ENST00000557589.1	n.1621C>T		non_coding_transcript_exon_variant	Exon 9 of 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

GnomAD2 exomes AF: 0.491 AC: 123363 AN: 251054 AF XY: 0.501

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 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

African (AFR) AF: 0.341 AC: 11403 AN: 33476

American (AMR) AF: 0.374 AC: 16704 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 12545 AN: 26134

East Asian (EAS) AF: 0.363 AC: 14403 AN: 39700

South Asian (SAS) AF: 0.498 AC: 42965 AN: 86238

European-Finnish (FIN) AF: 0.614 AC: 32801 AN: 53416

Middle Eastern (MID) AF: 0.400 AC: 2310 AN: 5768

European-Non Finnish (NFE) AF: 0.570 AC: 633670 AN: 1111888

Other (OTH) AF: 0.517 AC: 31208 AN: 60390

GnomAD4 genome AF: 0.482 AC: 73309 AN: 151958 Hom.: 18702 Cov.: 31 AF XY: 0.485 AC XY: 36037 AN XY: 74254

African (AFR) AF: 0.352 AC: 14597 AN: 41422

American (AMR) AF: 0.432 AC: 6604 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1636 AN: 3468

East Asian (EAS) AF: 0.297 AC: 1530 AN: 5148

South Asian (SAS) AF: 0.490 AC: 2354 AN: 4804

European-Finnish (FIN) AF: 0.632 AC: 6667 AN: 10546

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38264 AN: 67978

Other (OTH) AF: 0.456 AC: 963 AN: 2114

Alfa AF: 0.536 Hom.: 76645

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;.
PhyloP100		9.3
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
Vest4		0.50
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
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

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