chr12-56448035-C-T

Variant names:

• chr12-56448035-C-T
• rs11171856
• NM_003920.5:c.-62+1275G>A

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+1275G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 151,934 control chromosomes in the GnomAD database, including 14,597 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 0.43 (14597 hom., cov: 31)
• Consequence: TIMELESS NM_003920.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0380
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5	c.-62+1275G>A		intron_variant	Intron 1 of 28	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2	c.-62+1275G>A		intron_variant	Intron 1 of 28		NP_001317224.1
TIMELESS	NR_138471.2	n.117+1275G>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+1275G>A		intron_variant	Intron 1 of 28	1	NM_003920.5	ENSP00000450607.1
TIMELESS	ENST00000229201.4	c.-62+1275G>A		intron_variant	Intron 1 of 28	5		ENSP00000229201.4

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65400 AN: 151816 Hom.: 14575 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.375

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

GnomAD4 genome AF: 0.431 AC: 65455 AN: 151934 Hom.: 14597 Cov.: 31 AF XY: 0.432 AC XY: 32045 AN XY: 74252

African (AFR) AF: 0.418 AC: 17315 AN: 41428

American (AMR) AF: 0.334 AC: 5091 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1173 AN: 3472

East Asian (EAS) AF: 0.251 AC: 1294 AN: 5148

South Asian (SAS) AF: 0.456 AC: 2193 AN: 4812

European-Finnish (FIN) AF: 0.522 AC: 5508 AN: 10542

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31522 AN: 67958

Other (OTH) AF: 0.379 AC: 801 AN: 2112

Alfa AF: 0.439 Hom.: 50104

Bravo AF: 0.408

Asia WGS AF: 0.387 AC: 1344 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.55
PhyloP100		-0.038
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: rs11171856; hg19: chr12-56841819;