rs10462021

Positions:

• chr1-7837073-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 0.16 (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

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=0.0020701885).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER3	NM_001377275.1	c.3473A>G	p.His1158Arg	missense_variant	21/22	ENST00000377532.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.3473A>G	p.His1158Arg	missense_variant	21/22	1	NM_001377275.1	A2

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

GnomAD3 exomes AF: 0.169 AC: 42547 AN: 251126 Hom.: 4125 AF XY: 0.171 AC XY: 23175 AN XY: 135734

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 SAS exome AF: 0.177

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

Gnomad4 AFR exome AF: 0.0875

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.0192

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.167

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

Gnomad4 AFR AF: 0.0896

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.150

Alfa AF: 0.176 Hom.: 6277

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 v4.3

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.47	T;T;.;T
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0	B;.;B;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

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: rs10462021; hg19: chr1-7897133; COSMIC: COSV62705901;