dbSNP rs2794664: PER3:c.-225+8C>A (chr1-7784384-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001377275.1(PER3):c.-225+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 150,108 control chromosomes in the GnomAD database, including 4,282 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4279 hom., cov: 31)

Exomes 𝑓: 0.12 ( 3 hom. )

Consequence

PER3
NM_001377275.1 splice_region, intron

Scores

Splicing: ADA: 0.0001362

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0770

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1 link	c.-225+8C>A		splice_region_variant, intron_variant	Intron 1 of 21	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PER3	ENST00000377532.8 link	c.-225+8C>A	splice_region_variant, intron_variant	Intron 1 of 21	1	NM_001377275.1	ENSP00000366755.3	P56645-2
PER3	ENST00000377541.5 link	c.-225+8C>A	splice_region_variant, intron_variant	Intron 1 of 9	1		ENSP00000366764.1	Q8TAR6
PER3	ENST00000614998.4 link	c.-309C>A	upstream_gene_variant		1		ENSP00000479223.1	A0A087WV69
PER3	ENST00000613533.4 link	c.-309C>A	upstream_gene_variant		5		ENSP00000482093.1	P56645-2

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33080

AN:

149472

Hom.:

4278

Cov.:

show subpopulations

Gnomad AFR

AF:

0.333

Gnomad AMI

AF:

0.141

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.235

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.0618

Gnomad MID

AF:

0.194

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.220

GnomAD4 exome

AF:

0.123

AC:

AN:

522

Hom.:

Cov.:

AF XY:

0.118

AC XY:

AN XY:

382

show subpopulations

African (AFR)

AF:

0.417

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.222

AC:

AN:

South Asian (SAS)

AF:

0.144

AC:

AN:

104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.104

AC:

AN:

366

Other (OTH)

AF:

0.0833

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.221

AC:

33104

AN:

149586

Hom.:

4279

Cov.:

AF XY:

0.216

AC XY:

15825

AN XY:

73244

show subpopulations

African (AFR)

AF:

0.333

AC:

13670

AN:

41068

American (AMR)

AF:

0.164

AC:

2487

AN:

15140

Ashkenazi Jewish (ASJ)

AF:

0.235

AC:

813

AN:

3454

East Asian (EAS)

AF:

0.385

AC:

1951

AN:

5066

South Asian (SAS)

AF:

0.289

AC:

1378

AN:

4774

European-Finnish (FIN)

AF:

0.0618

AC:

635

AN:

10278

Middle Eastern (MID)

AF:

0.197

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.173

AC:

11538

AN:

66590

Other (OTH)

AF:

0.219

AC:

455

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1252

2504

3756

5008

6260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0485

Hom.:

Bravo

AF:

0.232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.8

(source)

DANN

Benign

0.64

PhyloP100

-0.077

PromoterAI

-0.012

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.018

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over