12-56418191-C-T

Variant names:

• chr12-56418191-C-T
• rs148897503
• NM_003920.5:c.3397G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003920.5(TIMELESS):​c.3397G>A​(p.Ala1133Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A1133P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.37
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30476856).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003920.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	NM_003920.5	MANE Select	c.3397G>A	p.Ala1133Thr	missense	Exon 27 of 29	NP_003911.2	Q9UNS1-1
	TIMELESS	NM_001330295.2		c.3394G>A	p.Ala1132Thr	missense	Exon 27 of 29	NP_001317224.1	Q9UNS1-2
	TIMELESS	NR_138471.2		n.3534G>A		non_coding_transcript_exon	Exon 27 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.3397G>A	p.Ala1133Thr	missense	Exon 27 of 29	ENSP00000450607.1	Q9UNS1-1
	TIMELESS	ENST00000865172.1		c.3418G>A	p.Ala1140Thr	missense	Exon 27 of 29	ENSP00000535231.1
	TIMELESS	ENST00000927926.1		c.3418G>A	p.Ala1140Thr	missense	Exon 27 of 29	ENSP00000597985.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.057
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.14
Sift	Benign	0.079	T
Sift4G	Uncertain	0.042	D
Polyphen		0.060	B
Vest4		0.32
MutPred		0.51		Gain of catalytic residue at Q1132 (P = 0.0739)
MVP		0.35
MPC		0.55
ClinPred		0.71	D
GERP RS		4.2
Varity_R		0.051
gMVP		0.53
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs148897503; hg19: chr12-56811975;