rs10876890

Variant names:

• chr12-56439967-A-T
• rs10876890
• NM_003920.5:c.-61-5736T>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.-61-5736T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 151,844 control chromosomes in the GnomAD database, including 24,281 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 0.55 (24281 hom., cov: 31)
• Consequence: TIMELESS NM_003920.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.-61-5736T>A		intron_variant	Intron 1 of 28	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.-61-5736T>A		intron_variant	Intron 1 of 28		NP_001317224.1
TIMELESS	NR_138471.2	n.118-5736T>A		intron_variant	Intron 1 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.-61-5736T>A		intron_variant	Intron 1 of 28	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.-61-5736T>A		intron_variant	Intron 1 of 28	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84081 AN: 151724 Hom.: 24233 Cov.: 31

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.486

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.554 AC: 84182 AN: 151844 Hom.: 24281 Cov.: 31 AF XY: 0.551 AC XY: 40899 AN XY: 74210

African (AFR) AF: 0.685 AC: 28343 AN: 41382

American (AMR) AF: 0.413 AC: 6295 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1579 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1393 AN: 5176

South Asian (SAS) AF: 0.500 AC: 2407 AN: 4816

European-Finnish (FIN) AF: 0.589 AC: 6195 AN: 10516

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36257 AN: 67950

Other (OTH) AF: 0.491 AC: 1033 AN: 2104

Alfa AF: 0.538 Hom.: 2747

Bravo AF: 0.539

Asia WGS AF: 0.441 AC: 1533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.89
DANN	Benign	0.50
PhyloP100		-1.0
Mutation Taster		=100/0	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: rs10876890; hg19: chr12-56833751;