12-56418000-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.3463G>A(p.Ala1155Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1155D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.591

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=0.007472396).
• BP6: Variant 12-56418000-C-T is Benign according to our data. Variant chr12-56418000-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2470126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.3463G>A	p.Ala1155Thr	missense_variant	28/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.3460G>A	p.Ala1154Thr	missense_variant	28/29
TIMELESS	NR_138471.2	n.3600G>A		non_coding_transcript_exon_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3463G>A	p.Ala1155Thr	missense_variant	28/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.3460G>A	p.Ala1154Thr	missense_variant	28/29	5		A2
TIMELESS	ENST00000557589.1	n.2031G>A		non_coding_transcript_exon_variant	12/13	2

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251468 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135908

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 727248

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152308 Hom.: 0 Cov.: 31 AF XY: 0.000698 AC XY: 52 AN XY: 74478

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.000593

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.16
Dann	Benign	0.80
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.28	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.0070
Sift	Benign	0.61	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0030	B;.
Vest4		0.075
MVP		0.21
MPC		0.11
ClinPred		0.0031	T
GERP RS		-4.8
Varity_R		0.015
gMVP		0.069

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: rs150055938; hg19: chr12-56811784; COSMIC: COSV57510706; COSMIC: COSV57510706;