chr12-56444961-G-A

Position:

• chr12-56444961-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.-62+4349C>T		intron_variant		ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.-62+4349C>T		intron_variant			NP_001317224.1
TIMELESS	NR_138471.2	n.117+4349C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.-62+4349C>T		intron_variant		1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.-62+4349C>T		intron_variant		5		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

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0764

Gnomad4 EAS AF: 0.0886

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0753

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.0864

Alfa AF: 0.0642 Hom.: 552

Bravo AF: 0.0690

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.9
DANN	Benign	0.46

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: rs774045; hg19: chr12-56838745;