dbSNP rs150812083: PER3:p.Pro415Thr (chr1-7809893-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001377275.1(PER3):c.1243C>A(p.Pro415Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. P415A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PER3
NM_001377275.1 missense, splice_region

Scores

Splicing: ADA: 0.8497

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.94

Publications

0 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:

LOC124903833 (HGNC:):

LOC124903833 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377275.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PER3	NM_001377275.1	MANE Select	c.1243C>A	p.Pro415Thr	missense splice_region	Exon 12 of 22	NP_001364204.1	P56645-2
PER3	NM_001289862.2		c.1243C>A	p.Pro415Thr	missense splice_region	Exon 12 of 22	NP_001276791.1	P56645-2
PER3	NM_001438696.1		c.1240C>A	p.Pro414Thr	missense splice_region	Exon 12 of 22	NP_001425625.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PER3	ENST00000377532.8	TSL:1 MANE Select	c.1243C>A	p.Pro415Thr	missense splice_region	Exon 12 of 22	ENSP00000366755.3	P56645-2
PER3	ENST00000361923.2	TSL:1	c.1240C>A	p.Pro414Thr	missense splice_region	Exon 11 of 21	ENSP00000355031.2	P56645-1
PER3	ENST00000614998.4	TSL:1	c.1243C>A	p.Pro415Thr	missense splice_region	Exon 12 of 23	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461286

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111696

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.0012

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.3

PhyloP100

6.9

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.59

MutPred

0.63

Loss of ubiquitination at K409 (P = 0.1264)

MVP

0.81

MPC

0.44

ClinPred

1.0

GERP RS

4.4

Varity_R

0.81

gMVP

0.73

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over