chr12-56422138-C-A

Position:

• chr12-56422138-C-A

Variant summary

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

The NM_003920.5(TIMELESS):​c.2492G>T​(p.Arg831Leu) 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. 12/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R831Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• 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 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=0.3827773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.2492G>T	p.Arg831Leu	missense_variant	20/29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.2489G>T	p.Arg830Leu	missense_variant	20/29		NP_001317224.1
TIMELESS	NR_138471.2	n.2629G>T		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>T	p.Arg831Leu	missense_variant	20/29	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.2489G>T	p.Arg830Leu	missense_variant	20/29	5		ENSP00000229201.4
TIMELESS	ENST00000555808.1	n.84G>T		non_coding_transcript_exon_variant	1/2	3
TIMELESS	ENST00000557589.1	n.611G>T		non_coding_transcript_exon_variant	6/13	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.097
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.072	T;T
Polyphen		0.13	B;.
Vest4		0.36
MutPred		0.58		Loss of disorder (P = 0.0562);.;
MVP		0.29
MPC		0.34
ClinPred		0.90	D
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.19
gMVP		0.44

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;