12-56418153-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003920.5(TIMELESS):c.3435G>A(p.Ala1145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,614,200 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (27 hom.)
• Consequence: TIMELESS NM_003920.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.20

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-56418153-C-T is Benign according to our data. Variant chr12-56418153-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 786421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.2 with no splicing effect.
• BS2: High AC in GnomAd at 647 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.3435G>A	p.Ala1145=	synonymous_variant	27/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.3432G>A	p.Ala1144=	synonymous_variant	27/29
TIMELESS	NR_138471.2	n.3572G>A		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3435G>A	p.Ala1145=	synonymous_variant	27/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.3432G>A	p.Ala1144=	synonymous_variant	27/29	5		A2
TIMELESS	ENST00000557589.1	n.2003G>A		non_coding_transcript_exon_variant	11/13	2

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 647 AN: 152200 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00397 AC: 998 AN: 251446 Hom.: 1 AF XY: 0.00404 AC XY: 549 AN XY: 135886

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00906

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00569 AC: 8319 AN: 1461882 Hom.: 27 Cov.: 32 AF XY: 0.00547 AC XY: 3976 AN XY: 727244

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00781

Gnomad4 NFE exome AF: 0.00664

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00425 AC: 648 AN: 152318 Hom.: 2 Cov.: 31 AF XY: 0.00473 AC XY: 352 AN XY: 74482

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00482 Hom.: 2

Bravo AF: 0.00383

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TIMELESS: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.57
Dann	Benign	0.36

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: rs61937716; hg19: chr12-56811937;