12-56421379-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003920.5(TIMELESS):c.2840G>A(p.Arg947Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,613,790 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R947W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015688539).
• BS2: High AC in GnomAd at 137 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.2840G>A	p.Arg947Gln	missense_variant	23/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.2837G>A	p.Arg946Gln	missense_variant	23/29
TIMELESS	NR_138471.2	n.2977G>A		non_coding_transcript_exon_variant	23/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.2840G>A	p.Arg947Gln	missense_variant	23/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.2837G>A	p.Arg946Gln	missense_variant	23/29	5		A2
TIMELESS	ENST00000557589.1	n.1192G>A		non_coding_transcript_exon_variant	8/13	2

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152056 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000916 AC: 230 AN: 251096 Hom.: 0 AF XY: 0.000906 AC XY: 123 AN XY: 135732

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00163 AC: 2383 AN: 1461616 Hom.: 3 Cov.: 34 AF XY: 0.00156 AC XY: 1134 AN XY: 727110

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.000928 AC XY: 69 AN XY: 74392

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.000858

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00153

EpiControl AF: 0.00178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.2840G>A (p.R947Q) alteration is located in exon 23 (coding exon 22) of the TIMELESS gene. This alteration results from a G to A substitution at nucleotide position 2840, causing the arginine (R) at amino acid position 947 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	D;.
Vest4		0.57
MVP		0.54
MPC		0.59
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.29
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144128641; hg19: chr12-56815163;