rs228654

Positions:

• chr1-7837168-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER3	NM_001377275.1	c.3549+19G>A		intron_variant		ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.3549+19G>A		intron_variant		1	NM_001377275.1	ENSP00000366755	A2

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

GnomAD3 exomes AF: 0.0867 AC: 21420 AN: 246922 Hom.: 1090 AF XY: 0.0907 AC XY: 12101 AN XY: 133480

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 SAS exome AF: 0.0994

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

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.0608

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.0610

Gnomad4 SAS exome AF: 0.0955

Gnomad4 FIN exome AF: 0.0765

Gnomad4 NFE exome AF: 0.0988

Gnomad4 OTH exome AF: 0.0907

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

Gnomad4 AFR AF: 0.0256

Gnomad4 AMR AF: 0.0713

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0466

Gnomad4 SAS AF: 0.0889

Gnomad4 FIN AF: 0.0738

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0840

Alfa AF: 0.0991 Hom.: 505

Bravo AF: 0.0732

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.42

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: rs228654; hg19: chr1-7897228; COSMIC: COSV62708065;