1-7785635-T-C

Variant names:

• chr1-7785635-T-C
• rs228729
• NM_001377275.1:c.274+49T>C

Variant summary

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

The NM_001377275.1(PER3):​c.274+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,539,780 control chromosomes in the GnomAD database, including 346,397 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 0.69 (36271 hom., cov: 32)
  • Exomes 𝑓: 0.67 (310126 hom.)
• Consequence: PER3 NM_001377275.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 45 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1	c.274+49T>C		intron_variant	Intron 3 of 21	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.274+49T>C		intron_variant	Intron 3 of 21	1	NM_001377275.1	ENSP00000366755.3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104395 AN: 151988 Hom.: 36227 Cov.: 32

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.659

GnomAD2 exomes AF: 0.690 AC: 157632 AN: 228582 AF XY: 0.680

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.828

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.666 AC: 924835 AN: 1387674 Hom.: 310126 Cov.: 20 AF XY: 0.663 AC XY: 456863 AN XY: 688980

African (AFR) AF: 0.751 AC: 23489 AN: 31262

American (AMR) AF: 0.815 AC: 32311 AN: 39658

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 15457 AN: 24382

East Asian (EAS) AF: 0.741 AC: 28670 AN: 38688

South Asian (SAS) AF: 0.643 AC: 51794 AN: 80566

European-Finnish (FIN) AF: 0.652 AC: 34055 AN: 52226

Middle Eastern (MID) AF: 0.581 AC: 3196 AN: 5504

European-Non Finnish (NFE) AF: 0.659 AC: 697733 AN: 1058044

Other (OTH) AF: 0.665 AC: 38130 AN: 57344

GnomAD4 genome AF: 0.687 AC: 104492 AN: 152106 Hom.: 36271 Cov.: 32 AF XY: 0.685 AC XY: 50895 AN XY: 74322

African (AFR) AF: 0.749 AC: 31063 AN: 41500

American (AMR) AF: 0.721 AC: 11025 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2160 AN: 3470

East Asian (EAS) AF: 0.749 AC: 3870 AN: 5166

South Asian (SAS) AF: 0.647 AC: 3120 AN: 4824

European-Finnish (FIN) AF: 0.631 AC: 6659 AN: 10560

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44596 AN: 67988

Other (OTH) AF: 0.655 AC: 1383 AN: 2110

Alfa AF: 0.669 Hom.: 104779

Bravo AF: 0.698

Asia WGS AF: 0.689 AC: 2393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.74
PhyloP100		-1.1
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: rs228729; hg19: chr1-7845695;