12-56444961-G-A

Variant names:

• chr12-56444961-G-A
• rs774045
• NM_003920.5:c.-62+4349C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003920.5(TIMELESS):​c.-62+4349C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 151,082 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.067 (422 hom., cov: 30)
• Consequence: TIMELESS NM_003920.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	NM_003920.5	MANE Select	c.-62+4349C>T		intron	N/A	NP_003911.2
	TIMELESS	NM_001330295.2		c.-62+4349C>T		intron	N/A	NP_001317224.1
	TIMELESS	NR_138471.2		n.117+4349C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMELESS	ENST00000553532.6	TSL:1 MANE Select	c.-62+4349C>T		intron	N/A	ENSP00000450607.1
	TIMELESS	ENST00000229201.4	TSL:5	c.-62+4349C>T		intron	N/A	ENSP00000229201.4

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10128 AN: 150962 Hom.: 422 Cov.: 30

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0764

Gnomad EAS AF: 0.0890

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0878

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

GnomAD4 genome AF: 0.0671 AC: 10133 AN: 151082 Hom.: 422 Cov.: 30 AF XY: 0.0710 AC XY: 5231 AN XY: 73662

African (AFR) AF: 0.0523 AC: 2150 AN: 41144

American (AMR) AF: 0.123 AC: 1853 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.0764 AC: 265 AN: 3468

East Asian (EAS) AF: 0.0886 AC: 457 AN: 5156

South Asian (SAS) AF: 0.113 AC: 540 AN: 4776

European-Finnish (FIN) AF: 0.0753 AC: 781 AN: 10366

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3805 AN: 67872

Other (OTH) AF: 0.0864 AC: 180 AN: 2084

Alfa AF: 0.0641 Hom.: 752

Bravo AF: 0.0690

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.9
DANN	Benign	0.46
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs774045; hg19: chr12-56838745;