rs2640909

Variant names:

• chr1-7830057-T-C
• rs2640909
• NM_001377275.1:c.3110T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1037V) has been classified as Uncertain significance.

• 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
• Publications: 54 publications found

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]

PER3 Gene-Disease associations (from GenCC):

• advanced sleep phase syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PER3	NM_001377275.1	c.3110T>C	p.Met1037Thr	missense_variant	Exon 19 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

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

GnomAD2 exomes AF: 0.139 AC: 25208 AN: 181200 AF XY: 0.135

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 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

African (AFR) AF: 0.0560 AC: 1634 AN: 29174

American (AMR) AF: 0.164 AC: 5636 AN: 34364

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 4565 AN: 20356

East Asian (EAS) AF: 0.0721 AC: 2802 AN: 38872

South Asian (SAS) AF: 0.200 AC: 13854 AN: 69432

European-Finnish (FIN) AF: 0.299 AC: 14836 AN: 49608

Middle Eastern (MID) AF: 0.192 AC: 938 AN: 4876

European-Non Finnish (NFE) AF: 0.136 AC: 97154 AN: 714078

Other (OTH) AF: 0.163 AC: 7521 AN: 46148

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

African (AFR) AF: 0.116 AC: 4748 AN: 40912

American (AMR) AF: 0.261 AC: 3963 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1032 AN: 3458

East Asian (EAS) AF: 0.0559 AC: 286 AN: 5112

South Asian (SAS) AF: 0.264 AC: 1263 AN: 4788

European-Finnish (FIN) AF: 0.314 AC: 3297 AN: 10492

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19707 AN: 67666

Other (OTH) AF: 0.233 AC: 487 AN: 2094

Alfa AF: 0.271 Hom.: 5722

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

Feb 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.21
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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