rs11171846

Positions:

• chr12-56434272-C-T

Variant summary

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

The NM_003920.5(TIMELESS):​c.-61-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0744 in 936,264 control chromosomes in the GnomAD database, including 3,250 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 0.064 (427 hom., cov: 32)
  • Exomes 𝑓: 0.076 (2823 hom.)
• Consequence: TIMELESS NM_003920.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508

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=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.-61-41G>A		intron_variant		ENST00000553532.6
TIMELESS	NM_001330295.2	c.-61-41G>A		intron_variant
TIMELESS	NR_138471.2	n.118-41G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.-61-41G>A		intron_variant		1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.-61-41G>A		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.0641 AC: 9753 AN: 152104 Hom.: 428 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0731

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0380

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.0904

GnomAD4 exome AF: 0.0764 AC: 59929 AN: 784042 Hom.: 2823 Cov.: 10 AF XY: 0.0757 AC XY: 30990 AN XY: 409506

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.0570

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.000115

Gnomad4 SAS exome AF: 0.0373

Gnomad4 FIN exome AF: 0.0583

Gnomad4 NFE exome AF: 0.0876

Gnomad4 OTH exome AF: 0.0819

GnomAD4 genome AF: 0.0640 AC: 9743 AN: 152222 Hom.: 427 Cov.: 32 AF XY: 0.0620 AC XY: 4612 AN XY: 74418

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0729

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0376

Gnomad4 FIN AF: 0.0575

Gnomad4 NFE AF: 0.0926

Gnomad4 OTH AF: 0.0890

Alfa AF: 0.0930 Hom.: 1538

Bravo AF: 0.0642

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.8
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs11171846; hg19: chr12-56828056;