rs774026

Variant names:

• chr12-56428214-A-G
• rs774026
• NM_003920.5:c.1578+22T>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.1578+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,558,304 control chromosomes in the GnomAD database, including 163,925 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 0.41 (14441 hom., cov: 32)
  • Exomes 𝑓: 0.45 (149484 hom.)
• Consequence: TIMELESS NM_003920.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.659
• Publications: 15 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.1578+22T>C		intron_variant	Intron 13 of 28	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.1575+22T>C		intron_variant	Intron 13 of 28		NP_001317224.1
TIMELESS	NR_138471.2	n.1756+22T>C		intron_variant	Intron 13 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.1578+22T>C		intron_variant	Intron 13 of 28	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.1575+22T>C		intron_variant	Intron 13 of 28	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62880 AN: 151854 Hom.: 14437 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.488

GnomAD2 exomes AF: 0.499 AC: 108414 AN: 217318 AF XY: 0.496

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.711

Gnomad ASJ exome AF: 0.519

Gnomad EAS exome AF: 0.742

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.497

GnomAD4 exome AF: 0.454 AC: 639025 AN: 1406334 Hom.: 149484 Cov.: 32 AF XY: 0.456 AC XY: 315998 AN XY: 693694

African (AFR) AF: 0.225 AC: 7043 AN: 31352

American (AMR) AF: 0.695 AC: 25229 AN: 36290

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 12255 AN: 23332

East Asian (EAS) AF: 0.671 AC: 26169 AN: 39004

South Asian (SAS) AF: 0.497 AC: 39460 AN: 79422

European-Finnish (FIN) AF: 0.423 AC: 22035 AN: 52048

Middle Eastern (MID) AF: 0.566 AC: 2969 AN: 5244

European-Non Finnish (NFE) AF: 0.441 AC: 476776 AN: 1081888

Other (OTH) AF: 0.469 AC: 27089 AN: 57754

GnomAD4 genome AF: 0.414 AC: 62894 AN: 151970 Hom.: 14441 Cov.: 32 AF XY: 0.418 AC XY: 31005 AN XY: 74254

African (AFR) AF: 0.239 AC: 9888 AN: 41456

American (AMR) AF: 0.576 AC: 8782 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1838 AN: 3468

East Asian (EAS) AF: 0.727 AC: 3750 AN: 5158

South Asian (SAS) AF: 0.499 AC: 2403 AN: 4814

European-Finnish (FIN) AF: 0.406 AC: 4281 AN: 10548

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30427 AN: 67974

Other (OTH) AF: 0.483 AC: 1017 AN: 2106

Alfa AF: 0.445 Hom.: 3024

Bravo AF: 0.429

Asia WGS AF: 0.557 AC: 1938 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs774026; hg19: chr12-56821998;