rs2640908

chr1-7829881-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001377275.1(PER3):c.2934C>T(p.Thr978=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,609,316 control chromosomes in the GnomAD database, including 36,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4342 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31701 hom.)
• Consequence: PER3 NM_001377275.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.367

Genes affected

PER3 (HGNC:8847): (period circadian regulator 3) This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been linked to sleep disorders. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-7829881-C-T is Benign according to our data. Variant chr1-7829881-C-T is described in ClinVar as [Benign]. Clinvar id is 3060144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.367 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER3	NM_001377275.1	c.2934C>T	p.Thr978=	synonymous_variant	19/22	ENST00000377532.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.2934C>T	p.Thr978=	synonymous_variant	19/22	1	NM_001377275.1	A2
PER3	ENST00000361923.2	c.2907C>T	p.Thr969=	synonymous_variant	18/21	1		P2
PER3	ENST00000614998.4	c.2931C>T	p.Thr977=	synonymous_variant	19/23	1		A2
PER3	ENST00000613533.4	c.2934C>T	p.Thr978=	synonymous_variant	19/22	5		A2

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33612 AN: 151832 Hom.: 4343 Cov.: 31

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.218 AC: 54510 AN: 250128 Hom.: 7245 AF XY: 0.219 AC XY: 29674 AN XY: 135316

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.493

Gnomad SAS exome AF: 0.287

Gnomad FIN exome AF: 0.0903

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.196 AC: 286196 AN: 1457366 Hom.: 31701 Cov.: 35 AF XY: 0.198 AC XY: 143836 AN XY: 725186

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.489

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.0920

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.221 AC: 33637 AN: 151950 Hom.: 4342 Cov.: 31 AF XY: 0.217 AC XY: 16086 AN XY: 74270

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.0811

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.217

Alfa AF: 0.194 Hom.: 4096

Bravo AF: 0.231

Asia WGS AF: 0.342 AC: 1187 AN: 3476

EpiCase AF: 0.186

EpiControl AF: 0.191

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PER3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.7
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2640908; hg19: chr1-7889941; COSMIC: COSV62706060; COSMIC: COSV62706060;