rs2794664

chr1-7784384-C-Achr1-7784384-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377275.1(PER3):c.-225+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 150,108 control chromosomes in the GnomAD database, including 4,282 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4279 hom., cov: 31)
  • Exomes 𝑓: 0.12 (3 hom.)
• Consequence: PER3 NM_001377275.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001362
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770

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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER3	NM_001377275.1	c.-225+8C>A		splice_region_variant, intron_variant		ENST00000377532.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.-225+8C>A		splice_region_variant, intron_variant		1	NM_001377275.1	A2
PER3	ENST00000377541.5	c.-225+8C>A		splice_region_variant, intron_variant		1
PER3	ENST00000614998.4			upstream_gene_variant		1		A2
PER3	ENST00000613533.4			upstream_gene_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33080 AN: 149472 Hom.: 4278 Cov.: 31

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.123 AC: 64 AN: 522 Hom.: 3 Cov.: 0 AF XY: 0.118 AC XY: 45 AN XY: 382

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.0833

GnomAD4 genome AF: 0.221 AC: 33104 AN: 149586 Hom.: 4279 Cov.: 31 AF XY: 0.216 AC XY: 15825 AN XY: 73244

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.0618

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.219

Alfa AF: 0.0485 Hom.: 53

Bravo AF: 0.232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	6.8
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.018

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2794664; hg19: chr1-7844444;