Genetic Variant NM_001377275.1:c.2504T>C (chr1-7827433-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001377275.1(PER3):c.2504T>C(p.Leu835Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,614,184 control chromosomes in the GnomAD database, including 745,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.97 ( 71045 hom., cov: 34)

Exomes 𝑓: 0.96 ( 674908 hom. )

Consequence

PER3
NM_001377275.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.951

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:

ENSG00000236266 (HGNC:):

ENSG00000236266 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2495445E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1 link	c.2504T>C	p.Leu835Pro	missense_variant	Exon 18 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.2504T>C	p.Leu835Pro	missense_variant	Exon 18 of 22	1	NM_001377275.1	ENSP00000366755.3		P56645-2

Frequencies

GnomAD3 genomes

AF:

0.966

AC:

146998

AN:

152236

Hom.:

70988

Cov.:

show subpopulations

Gnomad AFR

AF:

0.972

Gnomad AMI

AF:

0.888

Gnomad AMR

AF:

0.971

Gnomad ASJ

AF:

0.976

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.979

Gnomad FIN

AF:

0.968

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.957

Gnomad OTH

AF:

0.964

GnomAD3 exomes

AF:

0.970

AC:

243853

AN:

251466

Hom.:

118264

AF XY:

0.969

AC XY:

131693

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.974

Gnomad AMR exome

AF:

0.986

Gnomad ASJ exome

AF:

0.974

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.978

Gnomad FIN exome

AF:

0.968

Gnomad NFE exome

AF:

0.957

Gnomad OTH exome

AF:

0.967

GnomAD4 exome

AF:

0.961

AC:

1404595

AN:

1461830

Hom.:

674908

Cov.:

AF XY:

0.961

AC XY:

699045

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.974

Gnomad4 AMR exome

AF:

0.984

Gnomad4 ASJ exome

AF:

0.975

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.977

Gnomad4 FIN exome

AF:

0.966

Gnomad4 NFE exome

AF:

0.956

Gnomad4 OTH exome

AF:

0.963

GnomAD4 genome

AF:

0.966

AC:

147114

AN:

152354

Hom.:

71045

Cov.:

AF XY:

0.966

AC XY:

71977

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.972

Gnomad4 AMR

AF:

0.971

Gnomad4 ASJ

AF:

0.976

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.979

Gnomad4 FIN

AF:

0.968

Gnomad4 NFE

AF:

0.957

Gnomad4 OTH

AF:

0.964

Alfa

AF:

0.960

Hom.:

109951

Bravo

AF:

0.966

TwinsUK

AF:

0.952

AC:

3531

ALSPAC

AF:

0.959

AC:

3695

ESP6500AA

AF:

0.973

AC:

4288

ESP6500EA

AF:

0.955

AC:

8211

ExAC

AF:

0.969

AC:

117630

Asia WGS

AF:

0.986

AC:

3429

AN:

3478

EpiCase

AF:

0.955

EpiControl

AF:

0.957

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.6

DANN

Benign

0.45

DEOGEN2

Benign

0.013

.;T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.16

T;T;.;T

MetaRNN

Benign

0.0000012

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.4

.;.;.;N

PrimateAI

Benign

0.30

PROVEAN

Benign

3.6

.;.;N;N

REVEL

Benign

0.047

Sift

Benign

0.50

.;.;T;T

Sift4G

Benign

0.38

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.090

MPC

0.14

ClinPred

0.0088

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.028

gMVP

0.16

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over