NM_001377275.1:c.1940T>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 59 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 -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	NM_001377275.1	MANE Select	c.1940T>G	p.Val647Gly	missense	Exon 16 of 22	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.1940T>G	p.Val647Gly	missense	Exon 16 of 22	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.1937T>G	p.Val646Gly	missense	Exon 16 of 22	NP_001425625.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.1940T>G	p.Val647Gly	missense	Exon 16 of 22	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.1916T>G	p.Val639Gly	missense	Exon 15 of 21	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.1940T>G	p.Val647Gly	missense	Exon 16 of 23	ENSP00000479223.1	A0A087WV69

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

GnomAD2 exomes AF: 0.169 AC: 42157 AN: 249028 AF XY: 0.170

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 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

African (AFR) AF: 0.0869 AC: 2905 AN: 33416

American (AMR) AF: 0.194 AC: 8610 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3810 AN: 26060

East Asian (EAS) AF: 0.0193 AC: 765 AN: 39654

South Asian (SAS) AF: 0.175 AC: 14998 AN: 85934

European-Finnish (FIN) AF: 0.241 AC: 12882 AN: 53400

Middle Eastern (MID) AF: 0.116 AC: 666 AN: 5758

European-Non Finnish (NFE) AF: 0.193 AC: 214621 AN: 1110466

Other (OTH) AF: 0.167 AC: 10043 AN: 60298

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

African (AFR) AF: 0.0893 AC: 3708 AN: 41540

American (AMR) AF: 0.189 AC: 2893 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3470

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5186

South Asian (SAS) AF: 0.174 AC: 836 AN: 4814

European-Finnish (FIN) AF: 0.240 AC: 2544 AN: 10588

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

European-Non Finnish (NFE) AF: 0.189 AC: 12864 AN: 67998

Other (OTH) AF: 0.151 AC: 318 AN: 2110

Alfa AF: 0.172 Hom.: 9125

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

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PER3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.79
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.68
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.95	P
Vest4		0.28
MPC		0.13
ClinPred		0.060	T
GERP RS		-6.9
Varity_R		0.18
gMVP		0.73
Mutation Taster		=98/2	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: rs10462020; hg19: chr1-7880683; COSMIC: COSV107451208;