Genetic Variant PER3:p.Thr1120Ile (chr1-7835906-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001377275.1(PER3):c.3359C>T(p.Thr1120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000696 in 1,611,220 control chromosomes in the GnomAD database, including 6 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).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 6 hom. )

Consequence

PER3
NM_001377275.1 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.69

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010260373).

BP6

Variant 1-7835906-C-T is Benign according to our data. Variant chr1-7835906-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039488.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1 link	c.3359C>T	p.Thr1120Ile	missense_variant	Exon 20 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PER3	ENST00000377532.8 link	c.3359C>T	p.Thr1120Ile	missense_variant	Exon 20 of 22	1	NM_001377275.1	ENSP00000366755.3	P56645-2
PER3	ENST00000361923.2 link	c.3332C>T	p.Thr1111Ile	missense_variant	Exon 19 of 21	1		ENSP00000355031.2	P56645-1
PER3	ENST00000614998.4 link	c.3302C>T	p.Thr1101Ile	missense_variant	Exon 21 of 23	1		ENSP00000479223.1	A0A087WV69
PER3	ENST00000613533.4 link	c.3359C>T	p.Thr1120Ile	missense_variant	Exon 20 of 22	5		ENSP00000482093.1	P56645-2

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00113

AC:

283

AN:

251232

Hom.:

AF XY:

0.00119

AC XY:

162

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000827

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000698

AC:

1018

AN:

1458886

Hom.:

Cov.:

AF XY:

0.000799

AC XY:

580

AN XY:

725970

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00330

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152334

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.000801

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00115

AC:

140

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PER3-related disorder

Benign:1

May 21, 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

0.17

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.0

DANN

Benign

0.93

DEOGEN2

Benign

0.29

.;T;.;T

Eigen

Benign

-0.0090

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.56

T;T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;.;.;M

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.0

.;.;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0050

.;.;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.99

D;.;D;D

Vest4

0.34

MVP

0.43

MPC

0.091

ClinPred

0.066

GERP RS

3.1

Varity_R

0.25

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over