12-56418153-C-T

Variant names:

• chr12-56418153-C-T
• rs61937716
• NM_003920.5:c.3435G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003920.5(TIMELESS):​c.3435G>A​(p.Ala1145Ala) 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:3
• 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

Our verdict: Benign. The variant received -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 GnomAd4 at 648 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.3435G>A	p.Ala1145Ala	synonymous_variant	Exon 27 of 29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.3432G>A	p.Ala1144Ala	synonymous_variant	Exon 27 of 29		NP_001317224.1
TIMELESS	NR_138471.2	n.3572G>A		non_coding_transcript_exon_variant	Exon 27 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3435G>A	p.Ala1145Ala	synonymous_variant	Exon 27 of 29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.3432G>A	p.Ala1144Ala	synonymous_variant	Exon 27 of 29	5		ENSP00000229201.4
TIMELESS	ENST00000557589.1	n.2003G>A		non_coding_transcript_exon_variant	Exon 11 of 13	2
TIMELESS	ENST00000553314.1	n.*137G>A		downstream_gene_variant		3

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

GnomAD2 exomes AF: 0.00397 AC: 998 AN: 251446 AF XY: 0.00404

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 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 AC: 37 AN: 33480

Gnomad4 AMR exome AF: 0.00262 AC: 117 AN: 44724

Gnomad4 ASJ exome AF: 0.000230 AC: 6 AN: 26136

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39700

Gnomad4 SAS exome AF: 0.000661 AC: 57 AN: 86258

Gnomad4 FIN exome AF: 0.00781 AC: 417 AN: 53418

Gnomad4 NFE exome AF: 0.00664 AC: 7380 AN: 1112002

Gnomad4 Remaining exome AF: 0.00495 AC: 299 AN: 60396

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 AC: 0.00132364 AN: 0.00132364

Gnomad4 AMR AF: 0.00627 AC: 0.00627123 AN: 0.00627123

Gnomad4 ASJ AF: 0.000288 AC: 0.000288184 AN: 0.000288184

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00104 AC: 0.00103605 AN: 0.00103605

Gnomad4 FIN AF: 0.00885 AC: 0.00885289 AN: 0.00885289

Gnomad4 NFE AF: 0.00563 AC: 0.00562937 AN: 0.00562937

Gnomad4 OTH AF: 0.00662 AC: 0.00662252 AN: 0.00662252

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TIMELESS: BP4, BP7 -

Jan 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.57
DANN	Benign	0.36
Mutation Taster		=100/0	polymorphism

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;