rs150812083

Positions:

chr1-7809893-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_001377275.1(PER3):c.1243C>G(p.Pro415Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00493 in 1,613,532 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0049 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0049 ( 44 hom. )

Consequence

PER3
NM_001377275.1 missense, splice_region

Scores

Splicing: ADA: 0.8318

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 6.94

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:

PER3 (HGNC:):

PER3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 1-7809893-C-G is Pathogenic according to our data. Variant chr1-7809893-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242410.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.009827554). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 754 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER3	NM_001377275.1 linkuse as main transcript	c.1243C>G	p.Pro415Ala	missense_variant, splice_region_variant	12/22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8 linkuse as main transcript	c.1243C>G	p.Pro415Ala	missense_variant, splice_region_variant	12/22	1	NM_001377275.1	ENSP00000366755.3		P56645-2

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

753

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00569

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00562

AC:

1406

AN:

249982

Hom.:

AF XY:

0.00568

AC XY:

768

AN XY:

135180

show subpopulations

Gnomad AFR exome

AF:

0.000680

Gnomad AMR exome

AF:

0.000842

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00236

Gnomad FIN exome

AF:

0.0290

Gnomad NFE exome

AF:

0.00568

Gnomad OTH exome

AF:

0.00427

GnomAD4 exome

AF:

0.00492

AC:

7194

AN:

1461188

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

3598

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000873

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00201

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.00475

Gnomad4 OTH exome

AF:

0.00421

GnomAD4 genome

AF:

0.00495

AC:

754

AN:

152344

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

425

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0290

Gnomad4 NFE

AF:

0.00569

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00467

Hom.:

Bravo

AF:

0.00267

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00581

AC:

705

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Advanced sleep phase syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Bioinformatics dept., Datar Cancer Genetics Limited, India

Jun 23, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

PER3: PS3:Moderate, PP4, BP4, BS1:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;.;D

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;.;D

MetaRNN

Benign

0.0098

T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

3.3

.;.;.;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.6

.;.;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.59

MVP

0.79

MPC

0.36

ClinPred

0.054

GERP RS

4.4

Varity_R

0.77

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Benign

0.65

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