rs2640909

Positions:

• chr1-7830057-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001377275.1(PER3):​c.3110T>C​(p.Met1037Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,157,842 control chromosomes in the GnomAD database, including 30,389 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (4680 hom., cov: 30)
  • Exomes 𝑓: 0.15 (25709 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.207

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044260025).
• BP6: Variant 1-7830057-T-C is Benign according to our data. Variant chr1-7830057-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3059597.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER3	NM_001377275.1	c.3110T>C	p.Met1037Thr	missense_variant	19/22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.3110T>C	p.Met1037Thr	missense_variant	19/22	1	NM_001377275.1	ENSP00000366755.3
PER3	ENST00000361923.2	c.3083T>C	p.Met1028Thr	missense_variant	18/21	1		ENSP00000355031.2
PER3	ENST00000614998.4	c.3053T>C	p.Met1018Thr	missense_variant	20/23	1		ENSP00000479223.1
PER3	ENST00000613533.4	c.3110T>C	p.Met1037Thr	missense_variant	19/22	5		ENSP00000482093.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35026 AN: 150816 Hom.: 4678 Cov.: 30

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.139 AC: 25208 AN: 181200 Hom.: 4762 AF XY: 0.135 AC XY: 12900 AN XY: 95346

Gnomad AFR exome AF: 0.0571

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0246

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.148 AC: 148940 AN: 1006908 Hom.: 25709 Cov.: 35 AF XY: 0.156 AC XY: 79573 AN XY: 509760

Gnomad4 AFR exome AF: 0.0560

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.0721

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.299

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.232 AC: 35055 AN: 150934 Hom.: 4680 Cov.: 30 AF XY: 0.233 AC XY: 17195 AN XY: 73722

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.0559

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.233

Alfa AF: 0.272 Hom.: 3685

Bravo AF: 0.223

TwinsUK AF: 0.287 AC: 1065

ALSPAC AF: 0.309 AC: 1189

ESP6500AA AF: 0.127 AC: 560

ESP6500EA AF: 0.295 AC: 2539

ExAC AF: 0.253 AC: 30691

Asia WGS AF: 0.0780 AC: 257 AN: 3292

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PER3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2019

This variant is classified as likely 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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.045
DANN	Benign	0.39
DEOGEN2	Benign	0.0082	.;T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.28	T;T;.;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	.;.;.;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.76	.;.;N;N
REVEL	Benign	0.011
Sift	Benign	0.20	.;.;T;T
Sift4G	Benign	0.94	T;T;T;T
Polyphen		0.017	B;.;B;B
Vest4		0.15
MPC		0.10
ClinPred		0.0045	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.20

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: rs2640909; hg19: chr1-7890117; COSMIC: COSV62704459; COSMIC: COSV62704459;