chr12-56420675-G-C

Position:

• chr12-56420675-G-C

Variant summary

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

The ENST00000553532.6(TIMELESS):​c.3122C>G​(p.Ala1041Gly) variant causes a missense change. 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. 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. A1041T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIMELESS ENST00000553532.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.41

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=0.24967271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.3122C>G	p.Ala1041Gly	missense_variant	26/29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.3119C>G	p.Ala1040Gly	missense_variant	26/29		NP_001317224.1
TIMELESS	NR_138471.2	n.3259C>G		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3122C>G	p.Ala1041Gly	missense_variant	26/29	1	NM_003920.5	ENSP00000450607	P4
TIMELESS	ENST00000229201.4	c.3119C>G	p.Ala1040Gly	missense_variant	26/29	5		ENSP00000229201	A2
TIMELESS	ENST00000553314.1	n.335C>G		non_coding_transcript_exon_variant	2/3	3
TIMELESS	ENST00000557589.1	n.1690C>G		non_coding_transcript_exon_variant	10/13	2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.3122C>G (p.A1041G) alteration is located in exon 26 (coding exon 25) of the TIMELESS gene. This alteration results from a C to G substitution at nucleotide position 3122, causing the alanine (A) at amino acid position 1041 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.032	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.98	D;D;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.091
Sift	Benign	0.55	T;T
Sift4G	Uncertain	0.053	T;T
Polyphen		0.39	B;.
Vest4		0.27
MutPred		0.63		Gain of catalytic residue at V1045 (P = 9e-04);.;
MVP		0.54
MPC		0.12
ClinPred		0.60	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-56814459;