rs2291738

Positions:

• chr12-56421497-T-C

Variant summary

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

The NM_003920.5(TIMELESS):​c.2726-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,604,318 control chromosomes in the GnomAD database, including 185,658 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (13223 hom., cov: 31)
  • Exomes 𝑓: 0.48 (172435 hom.)
• Consequence: TIMELESS NM_003920.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001265
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34

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 (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.2726-4A>G		splice_region_variant, intron_variant		ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.2723-4A>G		splice_region_variant, intron_variant			NP_001317224.1
TIMELESS	NR_138471.2	n.2863-4A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.2726-4A>G		splice_region_variant, intron_variant		1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.2723-4A>G		splice_region_variant, intron_variant		5		ENSP00000229201.4
TIMELESS	ENST00000557589.1	n.1074A>G		non_coding_transcript_exon_variant	8/13	2

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59511 AN: 151832 Hom.: 13213 Cov.: 31

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.429 AC: 105462 AN: 245794 Hom.: 24242 AF XY: 0.441 AC XY: 58574 AN XY: 132946

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.320

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.288

Gnomad SAS exome AF: 0.479

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.439

GnomAD4 exome AF: 0.481 AC: 698614 AN: 1452368 Hom.: 172435 Cov.: 47 AF XY: 0.482 AC XY: 347662 AN XY: 721362

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.388

Gnomad4 EAS exome AF: 0.363

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.503

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.392 AC: 59542 AN: 151950 Hom.: 13223 Cov.: 31 AF XY: 0.397 AC XY: 29497 AN XY: 74250

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.362

Alfa AF: 0.450 Hom.: 16494

Bravo AF: 0.361

Asia WGS AF: 0.397 AC: 1378 AN: 3478

EpiCase AF: 0.472

EpiControl AF: 0.463

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs2291738; hg19: chr12-56815281; COSMIC: COSV57515002; COSMIC: COSV57515002;