NM_003920.5:c.2492G>A

Variant names:

• chr12-56422138-C-T
• rs774047
• NM_003920.5:c.2492G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003920.5(TIMELESS):​c.2492G>A​(p.Arg831Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 1,613,714 control chromosomes in the GnomAD database, including 170,547 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (14438 hom., cov: 31)
  • Exomes 𝑓: 0.46 (156109 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.103
• Publications: 50 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=1.4649072E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	NM_003920.5	MANE Select	c.2492G>A	p.Arg831Gln	missense	Exon 20 of 29	NP_003911.2	Q9UNS1-1
	TIMELESS	NM_001330295.2		c.2489G>A	p.Arg830Gln	missense	Exon 20 of 29	NP_001317224.1	Q9UNS1-2
	TIMELESS	NR_138471.2		n.2629G>A		non_coding_transcript_exon	Exon 20 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.2492G>A	p.Arg831Gln	missense	Exon 20 of 29	ENSP00000450607.1	Q9UNS1-1
	TIMELESS	ENST00000865172.1		c.2513G>A	p.Arg838Gln	missense	Exon 20 of 29	ENSP00000535231.1
	TIMELESS	ENST00000927926.1		c.2513G>A	p.Arg838Gln	missense	Exon 20 of 29	ENSP00000597985.1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62857 AN: 151810 Hom.: 14433 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.502 AC: 126228 AN: 251314 AF XY: 0.498

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.743

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.455 AC: 665696 AN: 1461786 Hom.: 156109 Cov.: 52 AF XY: 0.456 AC XY: 331947 AN XY: 727208

African (AFR) AF: 0.225 AC: 7545 AN: 33480

American (AMR) AF: 0.698 AC: 31209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 13753 AN: 26134

East Asian (EAS) AF: 0.671 AC: 26626 AN: 39696

South Asian (SAS) AF: 0.498 AC: 42959 AN: 86250

European-Finnish (FIN) AF: 0.423 AC: 22590 AN: 53408

Middle Eastern (MID) AF: 0.565 AC: 3257 AN: 5766

European-Non Finnish (NFE) AF: 0.440 AC: 489395 AN: 1111934

Other (OTH) AF: 0.470 AC: 28362 AN: 60394

GnomAD4 genome AF: 0.414 AC: 62874 AN: 151928 Hom.: 14438 Cov.: 31 AF XY: 0.418 AC XY: 31016 AN XY: 74214

African (AFR) AF: 0.239 AC: 9893 AN: 41454

American (AMR) AF: 0.576 AC: 8793 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1841 AN: 3472

East Asian (EAS) AF: 0.727 AC: 3759 AN: 5168

South Asian (SAS) AF: 0.501 AC: 2412 AN: 4810

European-Finnish (FIN) AF: 0.407 AC: 4276 AN: 10508

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30372 AN: 67940

Other (OTH) AF: 0.484 AC: 1019 AN: 2106

Alfa AF: 0.448 Hom.: 72430

Bravo AF: 0.428

TwinsUK AF: 0.417 AC: 1547

ALSPAC AF: 0.441 AC: 1699

ESP6500AA AF: 0.245 AC: 1078

ESP6500EA AF: 0.453 AC: 3895

ExAC AF: 0.490 AC: 59445

Asia WGS AF: 0.560 AC: 1949 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		-0.10
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.062
Sift	Benign	0.45	T
Sift4G	Benign	0.50	T
Polyphen		0.0050	B
Vest4		0.066
MPC		0.14
ClinPred		0.0083	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.029
gMVP		0.21
Mutation Taster		=93/7	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: rs774047; hg19: chr12-56815922; COSMIC: COSV57510939; COSMIC: COSV57510939;