chr12-56428594-T-A

Position:

• chr12-56428594-T-A

Variant summary

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

The NM_003920.5(TIMELESS):​c.1363A>T​(p.Ile455Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,613,532 control chromosomes in the GnomAD database, including 172,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (14833 hom., cov: 31)
  • Exomes 𝑓: 0.46 (157236 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.566

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 (MetaRNN=8.541583E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.1363A>T	p.Ile455Leu	missense_variant	12/29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.1360A>T	p.Ile454Leu	missense_variant	12/29		NP_001317224.1
TIMELESS	NR_138471.2	n.1541A>T		non_coding_transcript_exon_variant	12/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.1363A>T	p.Ile455Leu	missense_variant	12/29	1	NM_003920.5	ENSP00000450607	P4
TIMELESS	ENST00000229201.4	c.1360A>T	p.Ile454Leu	missense_variant	12/29	5		ENSP00000229201	A2

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64203 AN: 151874 Hom.: 14825 Cov.: 31

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.498

GnomAD3 exomes AF: 0.505 AC: 126268 AN: 249882 Hom.: 34176 AF XY: 0.500 AC XY: 67559 AN XY: 135106

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.714

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.748

Gnomad SAS exome AF: 0.499

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.457 AC: 668422 AN: 1461540 Hom.: 157236 Cov.: 48 AF XY: 0.458 AC XY: 333156 AN XY: 727078

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.701

Gnomad4 ASJ exome AF: 0.527

Gnomad4 EAS exome AF: 0.673

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.441

Gnomad4 OTH exome AF: 0.474

GnomAD4 genome AF: 0.423 AC: 64231 AN: 151992 Hom.: 14833 Cov.: 31 AF XY: 0.426 AC XY: 31647 AN XY: 74296

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.581

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.733

Gnomad4 SAS AF: 0.503

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.494

Alfa AF: 0.453 Hom.: 5476

Bravo AF: 0.438

TwinsUK AF: 0.418 AC: 1549

ALSPAC AF: 0.441 AC: 1701

ESP6500AA AF: 0.270 AC: 1188

ESP6500EA AF: 0.454 AC: 3907

ExAC AF: 0.493 AC: 59829

Asia WGS AF: 0.570 AC: 1985 AN: 3478

EpiCase AF: 0.458

EpiControl AF: 0.467

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.5
DANN	Benign	0.42
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.32	T;T
MetaRNN	Benign	8.5e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.73	N;N
REVEL	Benign	0.016
Sift	Benign	0.53	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	B;B
Vest4		0.077
MutPred		0.33		Gain of catalytic residue at M453 (P = 0.0075);.;
MPC		0.11
ClinPred		0.000015	T
GERP RS		-2.3
Varity_R		0.033
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774027; hg19: chr12-56822378; COSMIC: COSV57511395; COSMIC: COSV57511395;