12-56417963-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003920.5(TIMELESS):c.3500A>C(p.Lys1167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26577717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.3500A>C	p.Lys1167Thr	missense_variant	28/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.3497A>C	p.Lys1166Thr	missense_variant	28/29
TIMELESS	NR_138471.2	n.3637A>C		non_coding_transcript_exon_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3500A>C	p.Lys1167Thr	missense_variant	28/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.3497A>C	p.Lys1166Thr	missense_variant	28/29	5		A2
TIMELESS	ENST00000557589.1	n.2068A>C		non_coding_transcript_exon_variant	12/13	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Aug 02, 2021

The c.3500A>C (p.K1167T) alteration is located in exon 28 (coding exon 27) of the TIMELESS gene. This alteration results from a A to C substitution at nucleotide position 3500, causing the lysine (K) at amino acid position 1167 to be replaced by a threonine (T). 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	0.18
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.98	D;D;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.12
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.87	P;.
Vest4		0.44
MutPred		0.42		Gain of phosphorylation at K1167 (P = 0.0033);.;
MVP		0.35
MPC		0.55
ClinPred		0.83	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56811747;