rs228654

Variant names:

• chr1-7837168-G-A
• rs228654
• NM_001377275.1:c.3549+19G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377275.1(PER3):​c.3549+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0927 in 1,606,904 control chromosomes in the GnomAD database, including 7,413 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (531 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6882 hom.)
• Consequence: PER3 NM_001377275.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 26 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	NM_001377275.1	MANE Select	c.3549+19G>A		intron	N/A	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.3549+19G>A		intron	N/A	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.3546+19G>A		intron	N/A	NP_001425625.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.3549+19G>A		intron	N/A	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.3522+19G>A		intron	N/A	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.3492+19G>A		intron	N/A	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes AF: 0.0747 AC: 11362 AN: 152080 Hom.: 530 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0713

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0849

GnomAD2 exomes AF: 0.0867 AC: 21420 AN: 246922 AF XY: 0.0907

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0735

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0946 AC: 137670 AN: 1454708 Hom.: 6882 Cov.: 29 AF XY: 0.0955 AC XY: 69147 AN XY: 723814

African (AFR) AF: 0.0233 AC: 774 AN: 33282

American (AMR) AF: 0.0608 AC: 2670 AN: 43934

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3985 AN: 25886

East Asian (EAS) AF: 0.0610 AC: 2417 AN: 39626

South Asian (SAS) AF: 0.0955 AC: 8152 AN: 85378

European-Finnish (FIN) AF: 0.0765 AC: 4080 AN: 53302

Middle Eastern (MID) AF: 0.136 AC: 769 AN: 5668

European-Non Finnish (NFE) AF: 0.0988 AC: 109370 AN: 1107514

Other (OTH) AF: 0.0907 AC: 5453 AN: 60118

GnomAD4 genome AF: 0.0747 AC: 11362 AN: 152196 Hom.: 531 Cov.: 32 AF XY: 0.0735 AC XY: 5471 AN XY: 74418

African (AFR) AF: 0.0256 AC: 1062 AN: 41554

American (AMR) AF: 0.0713 AC: 1088 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 492 AN: 3468

East Asian (EAS) AF: 0.0466 AC: 241 AN: 5174

South Asian (SAS) AF: 0.0889 AC: 428 AN: 4812

European-Finnish (FIN) AF: 0.0738 AC: 783 AN: 10606

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6947 AN: 68000

Other (OTH) AF: 0.0840 AC: 177 AN: 2106

Alfa AF: 0.0961 Hom.: 653

Bravo AF: 0.0732

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.42
PhyloP100		0.078
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: rs228654; hg19: chr1-7897228; COSMIC: COSV62708065;