rs228697

Positions:

• chr1-7827519-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.2590C>G​(p.Pro864Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0931 in 1,614,104 control chromosomes in the GnomAD database, including 7,495 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.074 (528 hom., cov: 33)
  • Exomes 𝑓: 0.095 (6967 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970

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 (MetaRNN=0.0017670989).
• 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.2590C>G	p.Pro864Ala	missense_variant	18/22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.2590C>G	p.Pro864Ala	missense_variant	18/22	1	NM_001377275.1	ENSP00000366755	A2
PER3	ENST00000361923.2	c.2566C>G	p.Pro856Ala	missense_variant	17/21	1		ENSP00000355031	P2
PER3	ENST00000614998.4	c.2590C>G	p.Pro864Ala	missense_variant	18/23	1		ENSP00000479223	A2
PER3	ENST00000613533.4	c.2590C>G	p.Pro864Ala	missense_variant	18/22	5		ENSP00000482093	A2

Frequencies

GnomAD3 genomes AF: 0.0736 AC: 11209 AN: 152200 Hom.: 528 Cov.: 33

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0708

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0466

Gnomad SAS AF: 0.0894

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0832

GnomAD3 exomes AF: 0.0866 AC: 21780 AN: 251468 Hom.: 1120 AF XY: 0.0905 AC XY: 12303 AN XY: 135920

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0448

Gnomad SAS exome AF: 0.0989

Gnomad FIN exome AF: 0.0736

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0952 AC: 139116 AN: 1461786 Hom.: 6967 Cov.: 36 AF XY: 0.0960 AC XY: 69847 AN XY: 727210

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.0612

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.0610

Gnomad4 SAS exome AF: 0.0958

Gnomad4 FIN exome AF: 0.0766

Gnomad4 NFE exome AF: 0.0995

Gnomad4 OTH exome AF: 0.0909

GnomAD4 genome AF: 0.0736 AC: 11206 AN: 152318 Hom.: 528 Cov.: 33 AF XY: 0.0723 AC XY: 5388 AN XY: 74482

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.0708

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0465

Gnomad4 SAS AF: 0.0893

Gnomad4 FIN AF: 0.0740

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0823

Alfa AF: 0.100 Hom.: 306

Bravo AF: 0.0719

TwinsUK AF: 0.0955 AC: 354

ALSPAC AF: 0.0970 AC: 374

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.104 AC: 897

ExAC AF: 0.0867 AC: 10523

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.86
DANN	Benign	0.65
DEOGEN2	Benign	0.038	.;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.54	T;T;.;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;.;.;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.7	.;.;D;D
REVEL	Benign	0.026
Sift	Benign	0.13	.;.;T;T
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.30	B;.;B;B
Vest4		0.070
MPC		0.082
ClinPred		0.013	T
GERP RS		-2.6
Varity_R		0.019
gMVP		0.17

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: rs228697; hg19: chr1-7887579; COSMIC: COSV62705754; COSMIC: COSV62705754;