1-7827519-C-G

Variant names:

• chr1-7827519-C-G
• rs228697
• NM_001377275.1:c.2590C>G

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P864R) has been classified as Uncertain significance.

• 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
• Publications: 76 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

ENSG00000236266 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PER3	NM_001377275.1	c.2590C>G	p.Pro864Ala	missense_variant	Exon 18 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.2590C>G	p.Pro864Ala	missense_variant	Exon 18 of 22	1	NM_001377275.1	ENSP00000366755.3

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

GnomAD2 exomes AF: 0.0866 AC: 21780 AN: 251468 AF XY: 0.0905

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 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

African (AFR) AF: 0.0189 AC: 634 AN: 33480

American (AMR) AF: 0.0612 AC: 2737 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 4035 AN: 26136

East Asian (EAS) AF: 0.0610 AC: 2422 AN: 39688

South Asian (SAS) AF: 0.0958 AC: 8264 AN: 86250

European-Finnish (FIN) AF: 0.0766 AC: 4092 AN: 53418

Middle Eastern (MID) AF: 0.135 AC: 779 AN: 5768

European-Non Finnish (NFE) AF: 0.0995 AC: 110663 AN: 1111930

Other (OTH) AF: 0.0909 AC: 5490 AN: 60392

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

African (AFR) AF: 0.0216 AC: 896 AN: 41574

American (AMR) AF: 0.0708 AC: 1083 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.0465 AC: 241 AN: 5184

South Asian (SAS) AF: 0.0893 AC: 431 AN: 4826

European-Finnish (FIN) AF: 0.0740 AC: 785 AN: 10612

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6959 AN: 68026

Other (OTH) AF: 0.0823 AC: 174 AN: 2114

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
PhyloP100		0.097
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
Mutation Taster		=97/3	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: rs228697; hg19: chr1-7887579; COSMIC: COSV62705754; COSMIC: COSV62705754;