Genetic Variant NM_003920.5:c.3262C>T (chr12-56418326-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003920.5(TIMELESS):c.3262C>T(p.Pro1088Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,498 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TIMELESS
NM_003920.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.093839675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMELESS	NM_003920.5 link	c.3262C>T	p.Pro1088Ser	missense_variant	Exon 27 of 29	ENST00000553532.6	NP_003911.2	Q9UNS1-1
TIMELESS	NM_001330295.2 link	c.3259C>T	p.Pro1087Ser	missense_variant	Exon 27 of 29		NP_001317224.1	Q9UNS1-2
TIMELESS	NR_138471.2 link	n.3399C>T		non_coding_transcript_exon_variant	Exon 27 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TIMELESS	ENST00000553532.6 link	c.3262C>T	p.Pro1088Ser	missense_variant	Exon 27 of 29	1	NM_003920.5	ENSP00000450607.1	Q9UNS1-1
TIMELESS	ENST00000229201.4 link	c.3259C>T	p.Pro1087Ser	missense_variant	Exon 27 of 29	5		ENSP00000229201.4	Q9UNS1-2
TIMELESS	ENST00000553314.1 link	n.475C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
TIMELESS	ENST00000557589.1 link	n.1830C>T		non_coding_transcript_exon_variant	Exon 11 of 13	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460498

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726556

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3262C>T (p.P1088S) alteration is located in exon 27 (coding exon 26) of the TIMELESS gene. This alteration results from a C to T substitution at nucleotide position 3262, causing the proline (P) at amino acid position 1088 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.41

DEOGEN2

Benign

0.071

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.041

Sift

Benign

0.99

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.093

B;.

Vest4

0.20

MutPred

0.43

Gain of catalytic residue at P1083 (P = 0.0032);.;

MVP

0.34

MPC

0.15

ClinPred

0.29

GERP RS

4.3

Varity_R

0.12

gMVP

0.36

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over