chr12-56433910-C-G

Variant names:

• chr12-56433910-C-G
• rs2279665
• NM_003920.5:c.114G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_003920.5(TIMELESS):​c.114G>C​(p.Leu38Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,613,744 control chromosomes in the GnomAD database, including 240,724 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 (23885 hom., cov: 32)
  • Exomes 𝑓: 0.54 (216839 hom.)
• Consequence: TIMELESS NM_003920.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• Publications: 24 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP7: Synonymous conserved (PhyloP=2.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.114G>C	p.Leu38Leu	synonymous_variant	Exon 3 of 29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.114G>C	p.Leu38Leu	synonymous_variant	Exon 3 of 29		NP_001317224.1
TIMELESS	NR_138471.2	n.292G>C		non_coding_transcript_exon_variant	Exon 3 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.114G>C	p.Leu38Leu	synonymous_variant	Exon 3 of 29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.114G>C	p.Leu38Leu	synonymous_variant	Exon 3 of 29	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83722 AN: 151932 Hom.: 23838 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.488 AC: 122516 AN: 250990 AF XY: 0.495

Gnomad AFR exome AF: 0.644

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.540 AC: 789104 AN: 1461694 Hom.: 216839 Cov.: 60 AF XY: 0.539 AC XY: 392209 AN XY: 727126

African (AFR) AF: 0.643 AC: 21538 AN: 33480

American (AMR) AF: 0.296 AC: 13259 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 12372 AN: 26136

East Asian (EAS) AF: 0.329 AC: 13069 AN: 39700

South Asian (SAS) AF: 0.503 AC: 43399 AN: 86256

European-Finnish (FIN) AF: 0.577 AC: 30786 AN: 53362

Middle Eastern (MID) AF: 0.425 AC: 2447 AN: 5764

European-Non Finnish (NFE) AF: 0.558 AC: 620695 AN: 1111878

Other (OTH) AF: 0.522 AC: 31539 AN: 60394

GnomAD4 genome AF: 0.551 AC: 83826 AN: 152050 Hom.: 23885 Cov.: 32 AF XY: 0.549 AC XY: 40823 AN XY: 74326

African (AFR) AF: 0.641 AC: 26553 AN: 41440

American (AMR) AF: 0.413 AC: 6307 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3468

East Asian (EAS) AF: 0.273 AC: 1410 AN: 5168

South Asian (SAS) AF: 0.501 AC: 2415 AN: 4818

European-Finnish (FIN) AF: 0.594 AC: 6279 AN: 10572

Middle Eastern (MID) AF: 0.448 AC: 130 AN: 290

European-Non Finnish (NFE) AF: 0.552 AC: 37503 AN: 67992

Other (OTH) AF: 0.495 AC: 1043 AN: 2106

Alfa AF: 0.539 Hom.: 7159

Bravo AF: 0.533

Asia WGS AF: 0.436 AC: 1514 AN: 3478

EpiCase AF: 0.542

EpiControl AF: 0.532

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2279665; hg19: chr12-56827694; COSMIC: COSV57509960;