NM_001377275.1:c.1940T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001377275.1(PER3):c.1940T>G(p.Val647Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,611,594 control chromosomes in the GnomAD database, including 28,217 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. V647L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 2128 hom., cov: 33)

Exomes 𝑓: 0.18 ( 26089 hom. )

Consequence

PER3
NM_001377275.1 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.678

Publications

59 publications found

Variant links:

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

PER3 links:

ENSG00000236266 (HGNC:):

ENSG00000236266 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054929256).

BP6

Variant 1-7820623-T-G is Benign according to our data. Variant chr1-7820623-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3059771.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1 link	c.1940T>G	p.Val647Gly	missense_variant	Exon 16 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8 link	c.1940T>G	p.Val647Gly	missense_variant	Exon 16 of 22	1	NM_001377275.1	ENSP00000366755.3		P56645-2

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23862

AN:

152074

Hom.:

2127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0890

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.240

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.151

GnomAD2 exomes

AF:

0.169

AC:

42157

AN:

249028

AF XY:

0.170

show subpopulations

Gnomad AFR exome

AF:

0.0899

Gnomad AMR exome

AF:

0.193

Gnomad ASJ exome

AF:

0.144

Gnomad EAS exome

AF:

0.00432

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.185

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.185

AC:

269300

AN:

1459402

Hom.:

26089

Cov.:

AF XY:

0.184

AC XY:

133607

AN XY:

725858

show subpopulations

African (AFR)

AF:

0.0869

AC:

2905

AN:

33416

American (AMR)

AF:

0.194

AC:

8610

AN:

44416

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

3810

AN:

26060

East Asian (EAS)

AF:

0.0193

AC:

765

AN:

39654

South Asian (SAS)

AF:

0.175

AC:

14998

AN:

85934

European-Finnish (FIN)

AF:

0.241

AC:

12882

AN:

53400

Middle Eastern (MID)

AF:

0.116

AC:

666

AN:

5758

European-Non Finnish (NFE)

AF:

0.193

AC:

214621

AN:

1110466

Other (OTH)

AF:

0.167

AC:

10043

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

9943

19887

29830

39774

49717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7484

14968

22452

29936

37420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.157

AC:

23892

AN:

152192

Hom.:

2128

Cov.:

AF XY:

0.159

AC XY:

11850

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0893

AC:

3708

AN:

41540

American (AMR)

AF:

0.189

AC:

2893

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

541

AN:

3470

East Asian (EAS)

AF:

0.0112

AC:

AN:

5186

South Asian (SAS)

AF:

0.174

AC:

836

AN:

4814

European-Finnish (FIN)

AF:

0.240

AC:

2544

AN:

10588

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.189

AC:

12864

AN:

67998

Other (OTH)

AF:

0.151

AC:

318

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1005

2009

3014

4018

5023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.172

Hom.:

9125

Bravo

AF:

0.147

TwinsUK

AF:

0.191

AC:

709

ALSPAC

AF:

0.211

AC:

814

ESP6500AA

AF:

0.0962

AC:

424

ESP6500EA

AF:

0.191

AC:

1643

ExAC

AF:

0.165

AC:

20087

Asia WGS

AF:

0.0700

AC:

243

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.183

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

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

0.14

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

.;T;.;D

Eigen

Benign

-0.79

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.68

T;T;.;T

MetaRNN

Benign

0.0055

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;.;.;M

PhyloP100

0.68

PrimateAI

Benign

0.21

PROVEAN

Pathogenic

-5.4

.;.;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0010

.;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.95

P;.;P;B

Vest4

0.28

MPC

0.13

ClinPred

0.060

GERP RS

-6.9

Varity_R

0.18

gMVP

0.73

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over