1-7837073-A-G

Variant names:

• chr1-7837073-A-G
• rs10462021
• NM_001377275.1:c.3473A>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.3473A>G​(p.His1158Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,613,086 control chromosomes in the GnomAD database, including 28,349 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2131 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26218 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 50 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 (MetaRNN=0.0020701885).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377275.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	NM_001377275.1	MANE Select	c.3473A>G	p.His1158Arg	missense	Exon 21 of 22	NP_001364204.1
	PER3	NM_001289862.2		c.3473A>G	p.His1158Arg	missense	Exon 21 of 22	NP_001276791.1
	PER3	NM_001438696.1		c.3470A>G	p.His1157Arg	missense	Exon 21 of 22	NP_001425625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.3473A>G	p.His1158Arg	missense	Exon 21 of 22	ENSP00000366755.3
	PER3	ENST00000361923.2	TSL:1	c.3446A>G	p.His1149Arg	missense	Exon 20 of 21	ENSP00000355031.2
	PER3	ENST00000614998.4	TSL:1	c.3416A>G	p.His1139Arg	missense	Exon 22 of 23	ENSP00000479223.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23881 AN: 152092 Hom.: 2130 Cov.: 32

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.169 AC: 42547 AN: 251126 AF XY: 0.171

Gnomad AFR exome AF: 0.0906

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.00419

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.185 AC: 270122 AN: 1460876 Hom.: 26218 Cov.: 32 AF XY: 0.184 AC XY: 134045 AN XY: 726730

African (AFR) AF: 0.0875 AC: 2927 AN: 33458

American (AMR) AF: 0.194 AC: 8660 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3817 AN: 26120

East Asian (EAS) AF: 0.0192 AC: 763 AN: 39658

South Asian (SAS) AF: 0.175 AC: 15053 AN: 86186

European-Finnish (FIN) AF: 0.241 AC: 12879 AN: 53390

Middle Eastern (MID) AF: 0.115 AC: 664 AN: 5762

European-Non Finnish (NFE) AF: 0.194 AC: 215294 AN: 1111304

Other (OTH) AF: 0.167 AC: 10065 AN: 60352

GnomAD4 genome AF: 0.157 AC: 23911 AN: 152210 Hom.: 2131 Cov.: 32 AF XY: 0.159 AC XY: 11856 AN XY: 74420

African (AFR) AF: 0.0896 AC: 3726 AN: 41562

American (AMR) AF: 0.190 AC: 2897 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3464

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5182

South Asian (SAS) AF: 0.174 AC: 843 AN: 4832

European-Finnish (FIN) AF: 0.240 AC: 2542 AN: 10578

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12859 AN: 67994

Other (OTH) AF: 0.150 AC: 317 AN: 2108

Alfa AF: 0.174 Hom.: 11994

Bravo AF: 0.148

TwinsUK AF: 0.192 AC: 713

ALSPAC AF: 0.212 AC: 817

ESP6500AA AF: 0.0960 AC: 423

ESP6500EA AF: 0.191 AC: 1644

ExAC AF: 0.166 AC: 20132

Asia WGS AF: 0.0710 AC: 245 AN: 3478

EpiCase AF: 0.184

EpiControl AF: 0.184

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.19
DANN	Benign	0.73
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.017
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.019
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.11
ClinPred		0.0026	T
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.048
Mutation Taster		=99/1	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: rs10462021; hg19: chr1-7897133; COSMIC: COSV62705901;