dbSNP rs369440957: PER3:p.Asp78Asn (chr1-7785544-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001377275.1(PER3):c.232G>A(p.Asp78Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D78H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PER3
NM_001377275.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.95

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22232738).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1 link	c.232G>A	p.Asp78Asn	missense_variant	Exon 3 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.232G>A	p.Asp78Asn	missense_variant	Exon 3 of 22	1	NM_001377275.1	ENSP00000366755.3		P56645-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

.;.;T;.;T

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.097

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.91

D;D;D;.;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L;.;L;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.4

N;.;.;N;N

REVEL

Benign

0.064

Sift

Benign

0.84

T;.;.;T;T

Sift4G

Benign

0.83

T;T;T;T;T

Polyphen

1.0, 1.0

.;D;.;D;D

Vest4

0.12

MutPred

0.32

Loss of ubiquitination at K73 (P = 0.0373);Loss of ubiquitination at K73 (P = 0.0373);Loss of ubiquitination at K73 (P = 0.0373);Loss of ubiquitination at K73 (P = 0.0373);Loss of ubiquitination at K73 (P = 0.0373);

MVP

0.50

MPC

0.37

ClinPred

0.81

GERP RS

3.0

Varity_R

0.052

gMVP

0.21

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

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