chr12-56418153-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
• Publications: 0 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 -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003920.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	NM_003920.5	MANE Select	c.3435G>A	p.Ala1145Ala	synonymous	Exon 27 of 29	NP_003911.2	Q9UNS1-1
	TIMELESS	NM_001330295.2		c.3432G>A	p.Ala1144Ala	synonymous	Exon 27 of 29	NP_001317224.1	Q9UNS1-2
	TIMELESS	NR_138471.2		n.3572G>A		non_coding_transcript_exon	Exon 27 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.3435G>A	p.Ala1145Ala	synonymous	Exon 27 of 29	ENSP00000450607.1	Q9UNS1-1
	TIMELESS	ENST00000865172.1		c.3456G>A	p.Ala1152Ala	synonymous	Exon 27 of 29	ENSP00000535231.1
	TIMELESS	ENST00000927926.1		c.3456G>A	p.Ala1152Ala	synonymous	Exon 27 of 29	ENSP00000597985.1

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

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86258

European-Finnish (FIN) AF: 0.00781 AC: 417 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00664 AC: 7380 AN: 1112002

Other (OTH) 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

African (AFR) AF: 0.00132 AC: 55 AN: 41552

American (AMR) AF: 0.00627 AC: 96 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00563 AC: 383 AN: 68036

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.57
DANN	Benign	0.36
PhyloP100		-3.2
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

Other links and lift over

dbSNP: rs61937716; hg19: chr12-56811937;