12-56443632-C-T

Variant names:

• chr12-56443632-C-T
• rs4630333
• NM_003920.5:c.-62+5678G>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+5678G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 152,062 control chromosomes in the GnomAD database, including 10,443 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 (10443 hom., cov: 31)
• Consequence: TIMELESS NM_003920.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.145

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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.-62+5678G>A		intron_variant	Intron 1 of 28	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.-62+5678G>A		intron_variant	Intron 1 of 28		NP_001317224.1
TIMELESS	NR_138471.2	n.117+5678G>A		intron_variant	Intron 1 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6	c.-62+5678G>A		intron_variant	Intron 1 of 28	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.-62+5678G>A		intron_variant	Intron 1 of 28	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51620 AN: 151944 Hom.: 10443 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.339 AC: 51620 AN: 152062 Hom.: 10443 Cov.: 31 AF XY: 0.340 AC XY: 25288 AN XY: 74340

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.644

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.396

Alfa AF: 0.383 Hom.: 1475

Bravo AF: 0.348

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.80

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: rs4630333; hg19: chr12-56837416;