12-56418146-C-T

Variant names:

• chr12-56418146-C-T
• rs868081171
• NM_003920.5:c.3442G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003920.5(TIMELESS):​c.3442G>A​(p.Ala1148Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.542

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08478537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.3442G>A	p.Ala1148Thr	missense_variant	Exon 27 of 29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.3439G>A	p.Ala1147Thr	missense_variant	Exon 27 of 29		NP_001317224.1
TIMELESS	NR_138471.2	n.3579G>A		non_coding_transcript_exon_variant	Exon 27 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3442G>A	p.Ala1148Thr	missense_variant	Exon 27 of 29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.3439G>A	p.Ala1147Thr	missense_variant	Exon 27 of 29	5		ENSP00000229201.4
TIMELESS	ENST00000557589.1	n.2010G>A		non_coding_transcript_exon_variant	Exon 11 of 13	2
TIMELESS	ENST00000553314.1	n.*144G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3442G>A (p.A1148T) alteration is located in exon 27 (coding exon 26) of the TIMELESS gene. This alteration results from a G to A substitution at nucleotide position 3442, causing the alanine (A) at amino acid position 1148 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	0.069
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.4
DANN	Benign	0.96
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.050
Sift	Benign	0.11	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0030	B;.
Vest4		0.064
MutPred		0.36		Gain of catalytic residue at L1147 (P = 0.0243);.;
MVP		0.28
MPC		0.11
ClinPred		0.060	T
GERP RS		3.1
Varity_R		0.028
gMVP		0.073

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: rs868081171; hg19: chr12-56811930;