12-56417765-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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

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 -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 id is 708383.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 465 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.3578G>A	p.Gly1193Glu	missense_variant	29/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.3575G>A	p.Gly1192Glu	missense_variant	29/29
TIMELESS	NR_138471.2	n.3715G>A		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3578G>A	p.Gly1193Glu	missense_variant	29/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.3575G>A	p.Gly1192Glu	missense_variant	29/29	5		A2
TIMELESS	ENST00000557589.1	n.2146G>A		non_coding_transcript_exon_variant	13/13	2

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

GnomAD3 exomes AF: 0.00301 AC: 756 AN: 251470 Hom.: 1 AF XY: 0.00313 AC XY: 426 AN XY: 135912

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 SAS exome AF: 0.000588

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

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00738

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00420

Gnomad4 OTH exome AF: 0.00341

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

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00439 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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.29	N;N
REVEL	Benign	0.12
Sift	Benign	0.50	T;T
Sift4G	Benign	0.85	T;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

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: rs151146974; hg19: chr12-56811549; COSMIC: COSV57510245; COSMIC: COSV57510245;