12-56422138-C-T

Position:

• chr12-56422138-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003920.5(TIMELESS):​c.2492G>A​(p.Arg831Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 1,613,714 control chromosomes in the GnomAD database, including 170,547 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.41 (14438 hom., cov: 31)
  • Exomes 𝑓: 0.46 (156109 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.103

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]

TIMELESS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4649072E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.2492G>A	p.Arg831Gln	missense_variant	20/29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.2489G>A	p.Arg830Gln	missense_variant	20/29		NP_001317224.1
TIMELESS	NR_138471.2	n.2629G>A		non_coding_transcript_exon_variant	20/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.2492G>A	p.Arg831Gln	missense_variant	20/29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.2489G>A	p.Arg830Gln	missense_variant	20/29	5		ENSP00000229201.4
TIMELESS	ENST00000555808.1	n.84G>A		non_coding_transcript_exon_variant	1/2	3
TIMELESS	ENST00000557589.1	n.611G>A		non_coding_transcript_exon_variant	6/13	2

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62857 AN: 151810 Hom.: 14433 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.489

GnomAD3 exomes AF: 0.502 AC: 126228 AN: 251314 Hom.: 34087 AF XY: 0.498 AC XY: 67594 AN XY: 135806

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.499

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.455 AC: 665696 AN: 1461786 Hom.: 156109 Cov.: 52 AF XY: 0.456 AC XY: 331947 AN XY: 727208

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.671

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.414 AC: 62874 AN: 151928 Hom.: 14438 Cov.: 31 AF XY: 0.418 AC XY: 31016 AN XY: 74214

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.727

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.484

Alfa AF: 0.457 Hom.: 39304

Bravo AF: 0.428

TwinsUK AF: 0.417 AC: 1547

ALSPAC AF: 0.441 AC: 1699

ESP6500AA AF: 0.245 AC: 1078

ESP6500EA AF: 0.453 AC: 3895

ExAC AF: 0.490 AC: 59445

Asia WGS AF: 0.560 AC: 1949 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.062
Sift	Benign	0.45	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0050	B;.
Vest4		0.066
MPC		0.14
ClinPred		0.0083	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.029
gMVP		0.21

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: rs774047; hg19: chr12-56815922; COSMIC: COSV57510939; COSMIC: COSV57510939;