NM_003920.5:c.2726-4A>G

Variant names:

• chr12-56421497-T-C
• rs2291738
• NM_003920.5:c.2726-4A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 52 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 (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.487 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	NM_003920.5	MANE Select	c.2726-4A>G		splice_region intron	N/A	NP_003911.2
	TIMELESS	NM_001330295.2		c.2723-4A>G		splice_region intron	N/A	NP_001317224.1
	TIMELESS	NR_138471.2		n.2863-4A>G		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.2726-4A>G		splice_region intron	N/A	ENSP00000450607.1
	TIMELESS	ENST00000557589.1	TSL:2	n.1074A>G		non_coding_transcript_exon	Exon 8 of 13
	TIMELESS	ENST00000229201.4	TSL:5	c.2723-4A>G		splice_region intron	N/A	ENSP00000229201.4

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

GnomAD2 exomes AF: 0.429 AC: 105462 AN: 245794 AF XY: 0.441

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 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

African (AFR) AF: 0.175 AC: 5777 AN: 33046

American (AMR) AF: 0.322 AC: 13914 AN: 43162

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 10035 AN: 25840

East Asian (EAS) AF: 0.363 AC: 14339 AN: 39552

South Asian (SAS) AF: 0.478 AC: 40779 AN: 85356

European-Finnish (FIN) AF: 0.544 AC: 29009 AN: 53348

Middle Eastern (MID) AF: 0.311 AC: 1782 AN: 5726

European-Non Finnish (NFE) AF: 0.503 AC: 556049 AN: 1106394

Other (OTH) AF: 0.449 AC: 26930 AN: 59944

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

African (AFR) AF: 0.194 AC: 8041 AN: 41422

American (AMR) AF: 0.372 AC: 5675 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1358 AN: 3466

East Asian (EAS) AF: 0.299 AC: 1545 AN: 5166

South Asian (SAS) AF: 0.472 AC: 2275 AN: 4818

European-Finnish (FIN) AF: 0.562 AC: 5926 AN: 10546

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33388 AN: 67956

Other (OTH) AF: 0.362 AC: 763 AN: 2110

Alfa AF: 0.451 Hom.: 23331

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.31
DANN	Benign	0.53
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2291738; hg19: chr12-56815281; COSMIC: COSV57515002; COSMIC: COSV57515002;