Variant 12-56428594-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003920.5(TIMELESS):c.1363A>G(p.Ile455Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I455L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TIMELESS
NM_003920.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.566

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019755512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TIMELESS	NM_003920.5 linkuse as main transcript	c.1363A>G	p.Ile455Val	missense_variant	12/29	ENST00000553532.6	NP_003911.2
TIMELESS	NM_001330295.2 linkuse as main transcript	c.1360A>G	p.Ile454Val	missense_variant	12/29		NP_001317224.1
TIMELESS	NR_138471.2 linkuse as main transcript	n.1541A>G		non_coding_transcript_exon_variant	12/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMELESS	ENST00000553532.6 linkuse as main transcript	c.1363A>G	p.Ile455Val	missense_variant	12/29	1	NM_003920.5	ENSP00000450607	P4	Q9UNS1-1
TIMELESS	ENST00000229201.4 linkuse as main transcript	c.1360A>G	p.Ile454Val	missense_variant	12/29	5		ENSP00000229201	A2	Q9UNS1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249882

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.89

DANN

Benign

0.32

DEOGEN2

Benign

0.043

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.35

T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.017

Sift

Benign

0.46

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0

B;B

Vest4

0.033

MutPred

0.33

Gain of catalytic residue at M453 (P = 0.0102);.;

MVP

0.20

MPC

0.095

ClinPred

0.031

GERP RS

-2.3

Varity_R

0.018

gMVP

0.099

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over