12-56417765-C-T

Variant names:

• chr12-56417765-C-T
• rs151146974
• NM_003920.5:c.3578G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003920.5(TIMELESS):​c.3578G>A​(p.Gly1193Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,614,092 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.427
• Publications: 12 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048228204).
• BP6: Variant 12-56417765-C-T is Benign according to our data. Variant chr12-56417765-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 708383.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 466 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.3578G>A	p.Gly1193Glu	missense	Exon 29 of 29	NP_003911.2	Q9UNS1-1
	TIMELESS	NM_001330295.2		c.3575G>A	p.Gly1192Glu	missense	Exon 29 of 29	NP_001317224.1	Q9UNS1-2
	TIMELESS	NR_138471.2		n.3715G>A		non_coding_transcript_exon	Exon 29 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.3578G>A	p.Gly1193Glu	missense	Exon 29 of 29	ENSP00000450607.1	Q9UNS1-1
	TIMELESS	ENST00000865172.1		c.3599G>A	p.Gly1200Glu	missense	Exon 29 of 29	ENSP00000535231.1
	TIMELESS	ENST00000927926.1		c.3599G>A	p.Gly1200Glu	missense	Exon 29 of 29	ENSP00000597985.1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00301 AC: 756 AN: 251470 AF XY: 0.00313

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00444

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00371 AC: 5421 AN: 1461882 Hom.: 17 Cov.: 31 AF XY: 0.00371 AC XY: 2695 AN XY: 727240

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00302 AC: 135 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00738 AC: 193 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86256

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00420 AC: 4668 AN: 1112004

Other (OTH) AF: 0.00341 AC: 206 AN: 60396

GnomAD4 genome AF: 0.00306 AC: 466 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74432

African (AFR) AF: 0.00118 AC: 49 AN: 41516

American (AMR) AF: 0.00334 AC: 51 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00420 Hom.: 2

Bravo AF: 0.00311

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00282 AC: 343

EpiCase AF: 0.00447

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.0
DANN	Benign	0.23
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.43
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.12
Sift	Benign	0.50	T
Sift4G	Benign	0.85	T
Polyphen		0.040	B
Vest4		0.046
MVP		0.24
MPC		0.15
ClinPred		0.0019	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.075
Mutation Taster		=98/2	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: rs151146974; hg19: chr12-56811549; COSMIC: COSV57510245; COSMIC: COSV57510245;