12-56420619-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP3 BP4_Strong BP6_Moderate BS1 BS2

The NM_003920.5(TIMELESS):c.3178T>C(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 (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (13 hom.)
• Consequence: TIMELESS NM_003920.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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]

ACMG classification

Verdict is Benign. Variant got -13 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_single_submitter, 1 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 GnomAd at 1065 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMELESS	NM_003920.5	c.3178T>C	p.Phe1060Leu	missense_variant	26/29	ENST00000553532.6
TIMELESS	NM_001330295.2	c.3175T>C	p.Phe1059Leu	missense_variant	26/29
TIMELESS	NR_138471.2	n.3315T>C		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMELESS	ENST00000553532.6	c.3178T>C	p.Phe1060Leu	missense_variant	26/29	1	NM_003920.5	P4
TIMELESS	ENST00000229201.4	c.3175T>C	p.Phe1059Leu	missense_variant	26/29	5		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: 1065 AN: 152144 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00196 AC: 494 AN: 251476 Hom.: 6 AF XY: 0.00136 AC XY: 185 AN XY: 135908

Gnomad AFR exome AF: 0.0239

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000820 AC: 1199 AN: 1461894 Hom.: 13 Cov.: 33 AF XY: 0.000719 AC XY: 523 AN XY: 727248

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152262 Hom.: 9 Cov.: 32 AF XY: 0.00638 AC XY: 475 AN XY: 74442

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00145 Hom.: 8

Bravo AF: 0.00795

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.065	T;T
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.74		Gain of catalytic residue at M1055 (P = 0.0595);.;
MVP		0.45
MPC		0.60
ClinPred		0.066	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.81

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: rs61748694; hg19: chr12-56814403;