12-56420619-A-G
Position:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000553532.6(TIMELESS):āc.3178T>Cā(p.Phe1060Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,156 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0070 ( 9 hom., cov: 32)
Exomes š: 0.00082 ( 13 hom. )
Consequence
TIMELESS
ENST00000553532.6 missense
ENST00000553532.6 missense
Scores
7
3
8
Clinical Significance
Conservation
PhyloP100: 8.90
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.011211604).
BP6
Variant 12-56420619-A-G is Benign according to our data. Variant chr12-56420619-A-G is described in ClinVar as [Benign]. Clinvar id is 776721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00701 (1068/152262) while in subpopulation AFR AF= 0.0242 (1004/41542). AF 95% confidence interval is 0.0229. There are 9 homozygotes in gnomad4. There are 475 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1068 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TIMELESS | NM_003920.5 | c.3178T>C | p.Phe1060Leu | missense_variant | 26/29 | ENST00000553532.6 | NP_003911.2 | |
TIMELESS | NM_001330295.2 | c.3175T>C | p.Phe1059Leu | missense_variant | 26/29 | NP_001317224.1 | ||
TIMELESS | NR_138471.2 | n.3315T>C | non_coding_transcript_exon_variant | 26/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TIMELESS | ENST00000553532.6 | c.3178T>C | p.Phe1060Leu | missense_variant | 26/29 | 1 | NM_003920.5 | ENSP00000450607 | P4 | |
TIMELESS | ENST00000229201.4 | c.3175T>C | p.Phe1059Leu | missense_variant | 26/29 | 5 | ENSP00000229201 | A2 | ||
TIMELESS | ENST00000553314.1 | n.391T>C | non_coding_transcript_exon_variant | 2/3 | 3 | |||||
TIMELESS | ENST00000557589.1 | n.1746T>C | non_coding_transcript_exon_variant | 10/13 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00700 AC: 1065AN: 152144Hom.: 9 Cov.: 32
GnomAD3 genomes
AF:
AC:
1065
AN:
152144
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00196 AC: 494AN: 251476Hom.: 6 AF XY: 0.00136 AC XY: 185AN XY: 135908
GnomAD3 exomes
AF:
AC:
494
AN:
251476
Hom.:
AF XY:
AC XY:
185
AN XY:
135908
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000820 AC: 1199AN: 1461894Hom.: 13 Cov.: 33 AF XY: 0.000719 AC XY: 523AN XY: 727248
GnomAD4 exome
AF:
AC:
1199
AN:
1461894
Hom.:
Cov.:
33
AF XY:
AC XY:
523
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00701 AC: 1068AN: 152262Hom.: 9 Cov.: 32 AF XY: 0.00638 AC XY: 475AN XY: 74442
GnomAD4 genome
AF:
AC:
1068
AN:
152262
Hom.:
Cov.:
32
AF XY:
AC XY:
475
AN XY:
74442
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
105
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
283
Asia WGS
AF:
AC:
7
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at M1055 (P = 0.0595);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at