12-56435308-T-C

Position:

• chr12-56435308-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000553532.6(TIMELESS):​c.-61-1077A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 151,484 control chromosomes in the GnomAD database, including 10,578 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 0.34 (10578 hom., cov: 30)
• Consequence: TIMELESS ENST00000553532.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.94

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.-61-1077A>G		intron_variant		ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.-61-1077A>G		intron_variant			NP_001317224.1
TIMELESS	NR_138471.2	n.118-1077A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.-61-1077A>G		intron_variant		1	NM_003920.5	ENSP00000450607	P4
TIMELESS	ENST00000229201.4	c.-61-1077A>G		intron_variant		5		ENSP00000229201	A2

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51832 AN: 151370 Hom.: 10577 Cov.: 30

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.411

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

GnomAD4 genome AF: 0.342 AC: 51830 AN: 151484 Hom.: 10578 Cov.: 30 AF XY: 0.343 AC XY: 25359 AN XY: 73996

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.382

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.406

Alfa AF: 0.409 Hom.: 22454

Bravo AF: 0.350

Asia WGS AF: 0.435 AC: 1513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0070
DANN	Benign	0.47

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: rs7302060; hg19: chr12-56829092;