NM_001377275.1:c.2259G>A

Variant names:

• chr1-7827188-G-A
• rs2859387
• NM_001377275.1:c.2259G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001377275.1(PER3):​c.2259G>A​(p.Pro753Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,610,900 control chromosomes in the GnomAD database, including 127,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.43 (14670 hom., cov: 32)
  • Exomes 𝑓: 0.38 (112481 hom.)
• Consequence: PER3 NM_001377275.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.16
• Publications: 23 publications found

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

ENSG00000236266 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-7827188-G-A is Benign according to our data. Variant chr1-7827188-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060684.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-3.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	NM_001377275.1	MANE Select	c.2259G>A	p.Pro753Pro	synonymous	Exon 18 of 22	NP_001364204.1
	PER3	NM_001289862.2		c.2259G>A	p.Pro753Pro	synonymous	Exon 18 of 22	NP_001276791.1
	PER3	NM_001438696.1		c.2256G>A	p.Pro752Pro	synonymous	Exon 18 of 22	NP_001425625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.2259G>A	p.Pro753Pro	synonymous	Exon 18 of 22	ENSP00000366755.3
	PER3	ENST00000361923.2	TSL:1	c.2235G>A	p.Pro745Pro	synonymous	Exon 17 of 21	ENSP00000355031.2
	PER3	ENST00000614998.4	TSL:1	c.2259G>A	p.Pro753Pro	synonymous	Exon 18 of 23	ENSP00000479223.1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64596 AN: 151852 Hom.: 14662 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.430 AC: 105731 AN: 245866 AF XY: 0.416

Gnomad AFR exome AF: 0.519

Gnomad AMR exome AF: 0.565

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.811

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.384 AC: 560026 AN: 1458930 Hom.: 112481 Cov.: 44 AF XY: 0.380 AC XY: 275859 AN XY: 725436

African (AFR) AF: 0.521 AC: 17390 AN: 33408

American (AMR) AF: 0.552 AC: 24493 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8415 AN: 26050

East Asian (EAS) AF: 0.759 AC: 30083 AN: 39636

South Asian (SAS) AF: 0.370 AC: 31816 AN: 86006

European-Finnish (FIN) AF: 0.349 AC: 18518 AN: 53034

Middle Eastern (MID) AF: 0.303 AC: 1745 AN: 5752

European-Non Finnish (NFE) AF: 0.363 AC: 403467 AN: 1110424

Other (OTH) AF: 0.400 AC: 24099 AN: 60258

GnomAD4 genome AF: 0.425 AC: 64652 AN: 151970 Hom.: 14670 Cov.: 32 AF XY: 0.424 AC XY: 31477 AN XY: 74270

African (AFR) AF: 0.517 AC: 21417 AN: 41440

American (AMR) AF: 0.450 AC: 6882 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4045 AN: 5130

South Asian (SAS) AF: 0.382 AC: 1842 AN: 4820

European-Finnish (FIN) AF: 0.334 AC: 3524 AN: 10566

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.363 AC: 24689 AN: 67950

Other (OTH) AF: 0.395 AC: 834 AN: 2112

Alfa AF: 0.358 Hom.: 2961

Bravo AF: 0.442

Asia WGS AF: 0.576 AC: 2002 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PER3-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.019
DANN	Benign	0.88
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2859387; hg19: chr1-7887248; COSMIC: COSV62707524;