Genetic Variant NM_001377275.1:c.2934C>T (chr1-7829881-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001377275.1(PER3):c.2934C>T(p.Thr978Thr) 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 (no stars).

Frequency

Genomes: 𝑓 0.22 ( 4342 hom., cov: 31)

Exomes 𝑓: 0.20 ( 31701 hom. )

Consequence

PER3
NM_001377275.1 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.367

Publications

42 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 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 VariationId is 3060144.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
PER3	NM_001377275.1 link	c.2934C>T	p.Thr978Thr	synonymous_variant	Exon 19 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PER3	ENST00000377532.8 link	c.2934C>T	p.Thr978Thr	synonymous_variant	Exon 19 of 22	1	NM_001377275.1	ENSP00000366755.3	P56645-2
PER3	ENST00000361923.2 link	c.2907C>T	p.Thr969Thr	synonymous_variant	Exon 18 of 21	1		ENSP00000355031.2	P56645-1
PER3	ENST00000614998.4 link	c.2931C>T	p.Thr977Thr	synonymous_variant	Exon 19 of 23	1		ENSP00000479223.1	A0A087WV69
PER3	ENST00000613533.4 link	c.2934C>T	p.Thr978Thr	synonymous_variant	Exon 19 of 22	5		ENSP00000482093.1	P56645-2

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33612

AN:

151832

Hom.:

4343

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.218

AC:

54510

AN:

250128

AF XY:

0.219

show subpopulations

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 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.:

AF XY:

0.198

AC XY:

143836

AN XY:

725186

show subpopulations

African (AFR)

AF:

0.311

AC:

10367

AN:

33376

American (AMR)

AF:

0.171

AC:

7626

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6342

AN:

26094

East Asian (EAS)

AF:

0.489

AC:

19361

AN:

39628

South Asian (SAS)

AF:

0.288

AC:

24772

AN:

86114

European-Finnish (FIN)

AF:

0.0920

AC:

4916

AN:

53414

Middle Eastern (MID)

AF:

0.242

AC:

1392

AN:

5760

European-Non Finnish (NFE)

AF:

0.179

AC:

198076

AN:

1108086

Other (OTH)

AF:

0.222

AC:

13344

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11592

23184

34777

46369

57961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7224

14448

21672

28896

36120

<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:

0.221

AC:

33637

AN:

151950

Hom.:

4342

Cov.:

AF XY:

0.217

AC XY:

16086

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.305

AC:

12612

AN:

41384

American (AMR)

AF:

0.165

AC:

2514

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.238

AC:

828

AN:

3472

East Asian (EAS)

AF:

0.473

AC:

2432

AN:

5142

South Asian (SAS)

AF:

0.297

AC:

1429

AN:

4816

European-Finnish (FIN)

AF:

0.0811

AC:

860

AN:

10604

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12289

AN:

67956

Other (OTH)

AF:

0.217

AC:

457

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1262

2524

3785

5047

6309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.196

Hom.:

5748

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: no assertion criteria provided

LINK: link

Submissions by phenotype

PER3-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Benign

0.50

PhyloP100

-0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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