rs10462020

Variant names:

• chr1-7820623-T-G
• rs10462020
• NM_001377275.1:c.1940T>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001377275.1(PER3):​c.1940T>G​(p.Val647Gly) 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 1,611,594 control chromosomes in the GnomAD database, including 28,217 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V647L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2128 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26089 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.678

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]

ENSG00000236266 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054929256).
• BP6: Variant 1-7820623-T-G is Benign according to our data. Variant chr1-7820623-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3059771.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 rank	MANE	Protein	UniProt
PER3	NM_001377275.1	c.1940T>G	p.Val647Gly	missense_variant	Exon 16 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.1940T>G	p.Val647Gly	missense_variant	Exon 16 of 22	1	NM_001377275.1	ENSP00000366755.3

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23862 AN: 152074 Hom.: 2127 Cov.: 33

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.173

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: 42157 AN: 249028 Hom.: 4049 AF XY: 0.170 AC XY: 22943 AN XY: 134576

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.00432

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.185 AC: 269300 AN: 1459402 Hom.: 26089 Cov.: 33 AF XY: 0.184 AC XY: 133607 AN XY: 725858

Gnomad4 AFR exome AF: 0.0869

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.0193

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.157 AC: 23892 AN: 152192 Hom.: 2128 Cov.: 33 AF XY: 0.159 AC XY: 11850 AN XY: 74416

Gnomad4 AFR AF: 0.0893

Gnomad4 AMR AF: 0.189

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: 0.151

Alfa AF: 0.174 Hom.: 4885

Bravo AF: 0.147

TwinsUK AF: 0.191 AC: 709

ALSPAC AF: 0.211 AC: 814

ESP6500AA AF: 0.0962 AC: 424

ESP6500EA AF: 0.191 AC: 1643

ExAC AF: 0.165 AC: 20087

Asia WGS AF: 0.0700 AC: 243 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.183

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PER3-related disorder Benign:1

Feb 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T;.;D
Eigen	Benign	-0.79
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.68	T;T;.;T
MetaRNN	Benign	0.0055	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;.;.;M
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.4	.;.;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.95	P;.;P;B
Vest4		0.28
MPC		0.13
ClinPred		0.060	T
GERP RS		-6.9
Varity_R		0.18
gMVP		0.73

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: rs10462020; hg19: chr1-7880683;