12-56418189-GGC-TGG

Variant names:

• chr12-56418189-GGC-TGG
• NM_003920.5:c.3397_3399delGCCinsCCA
• TIMELESS p.Ala1133Pro

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003920.5(TIMELESS):​c.3397_3399delGCCinsCCA​(p.Ala1133Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49
• 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 0 ACMG points.

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.3397_3399delGCCinsCCA	p.Ala1133Pro	missense	N/A	NP_003911.2	Q9UNS1-1
	TIMELESS	NM_001330295.2		c.3394_3396delGCCinsCCA	p.Ala1132Pro	missense	N/A	NP_001317224.1	Q9UNS1-2
	TIMELESS	NR_138471.2		n.3534_3536delGCCinsCCA		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.3397_3399delGCCinsCCA	p.Ala1133Pro	missense	N/A	ENSP00000450607.1	Q9UNS1-1
	TIMELESS	ENST00000865172.1		c.3418_3420delGCCinsCCA	p.Ala1140Pro	missense	N/A	ENSP00000535231.1
	TIMELESS	ENST00000927926.1		c.3418_3420delGCCinsCCA	p.Ala1140Pro	missense	N/A	ENSP00000597985.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-56811973;