rs228669

Variant names:

• chr1-7809988-T-C
• rs228669
• NM_001377275.1:c.1338T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001377275.1(PER3):​c.1338T>C​(p.Ser446Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.917 in 1,613,778 control chromosomes in the GnomAD database, including 681,373 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 0.92 (64581 hom., cov: 32)
  • Exomes 𝑓: 0.92 (616792 hom.)
• Consequence: PER3 NM_001377275.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.441
• Publications: 37 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

LOC124903833 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=-0.441 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1	c.1338T>C	p.Ser446Ser	synonymous_variant	Exon 12 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.1338T>C	p.Ser446Ser	synonymous_variant	Exon 12 of 22	1	NM_001377275.1	ENSP00000366755.3

Frequencies

GnomAD3 genomes AF: 0.918 AC: 139666 AN: 152162 Hom.: 64532 Cov.: 32

Gnomad AFR AF: 0.964

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.946

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.910

GnomAD2 exomes AF: 0.880 AC: 221176 AN: 251212 AF XY: 0.891

Gnomad AFR exome AF: 0.966

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.940

Gnomad EAS exome AF: 0.715

Gnomad FIN exome AF: 0.957

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.917 AC: 1340096 AN: 1461498 Hom.: 616792 Cov.: 44 AF XY: 0.919 AC XY: 667917 AN XY: 727098

African (AFR) AF: 0.968 AC: 32390 AN: 33468

American (AMR) AF: 0.668 AC: 29877 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 24600 AN: 26130

East Asian (EAS) AF: 0.763 AC: 30274 AN: 39686

South Asian (SAS) AF: 0.937 AC: 80855 AN: 86252

European-Finnish (FIN) AF: 0.952 AC: 50882 AN: 53420

Middle Eastern (MID) AF: 0.939 AC: 5404 AN: 5756

European-Non Finnish (NFE) AF: 0.927 AC: 1030848 AN: 1111692

Other (OTH) AF: 0.910 AC: 54966 AN: 60372

GnomAD4 genome AF: 0.918 AC: 139771 AN: 152280 Hom.: 64581 Cov.: 32 AF XY: 0.915 AC XY: 68136 AN XY: 74456

African (AFR) AF: 0.964 AC: 40080 AN: 41568

American (AMR) AF: 0.781 AC: 11949 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 3284 AN: 3472

East Asian (EAS) AF: 0.725 AC: 3745 AN: 5166

South Asian (SAS) AF: 0.938 AC: 4524 AN: 4824

European-Finnish (FIN) AF: 0.958 AC: 10171 AN: 10612

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.927 AC: 63053 AN: 68022

Other (OTH) AF: 0.910 AC: 1926 AN: 2116

Alfa AF: 0.923 Hom.: 45523

Bravo AF: 0.902

Asia WGS AF: 0.819 AC: 2848 AN: 3478

EpiCase AF: 0.924

EpiControl AF: 0.926

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.29
DANN	Benign	0.35
PhyloP100		-0.44
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: rs228669; hg19: chr1-7870048; COSMIC: COSV62707152; COSMIC: COSV62707152;