rs228669

Positions:

• chr1-7809988-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001377275.1(PER3):​c.1338T>C​(p.Ser446=) 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

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]

LOC124903833 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PER3	NM_001377275.1	c.1338T>C	p.Ser446=	synonymous_variant	12/22	ENST00000377532.8
LOC124903833	XR_007065450.1	n.1689A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.1338T>C	p.Ser446=	synonymous_variant	12/22	1	NM_001377275.1	A2

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

GnomAD3 exomes AF: 0.880 AC: 221176 AN: 251212 Hom.: 99019 AF XY: 0.891 AC XY: 121057 AN XY: 135792

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 SAS exome AF: 0.939

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

Gnomad4 AFR exome AF: 0.968

Gnomad4 AMR exome AF: 0.668

Gnomad4 ASJ exome AF: 0.941

Gnomad4 EAS exome AF: 0.763

Gnomad4 SAS exome AF: 0.937

Gnomad4 FIN exome AF: 0.952

Gnomad4 NFE exome AF: 0.927

Gnomad4 OTH exome AF: 0.910

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

Gnomad4 AFR AF: 0.964

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.946

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.938

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.927

Gnomad4 OTH AF: 0.910

Alfa AF: 0.930 Hom.: 34912

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs228669; hg19: chr1-7870048; COSMIC: COSV62707152; COSMIC: COSV62707152;