1-7827174-C-T

Variant names:

• chr1-7827174-C-T
• rs35687686
• NM_001377275.1:c.2245C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001377275.1(PER3):​c.2245C>T​(p.Arg749Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,612,146 control chromosomes in the GnomAD database, including 21 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (11 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.686
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005526483).
• BP6: Variant 1-7827174-C-T is Benign according to our data. Variant chr1-7827174-C-T is described in ClinVar as Benign. ClinVar VariationId is 780748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00623 (949/152288) while in subpopulation AFR AF = 0.0215 (894/41562). AF 95% confidence interval is 0.0203. There are 10 homozygotes in GnomAd4. There are 456 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 949 AD gene.

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.2245C>T	p.Arg749Trp	missense	Exon 18 of 22	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.2245C>T	p.Arg749Trp	missense	Exon 18 of 22	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.2242C>T	p.Arg748Trp	missense	Exon 18 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.2245C>T	p.Arg749Trp	missense	Exon 18 of 22	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.2221C>T	p.Arg741Trp	missense	Exon 17 of 21	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.2245C>T	p.Arg749Trp	missense	Exon 18 of 23	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 949 AN: 152170 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00149 AC: 366 AN: 245374 AF XY: 0.00110

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.000643

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000656 AC: 957 AN: 1459858 Hom.: 11 Cov.: 30 AF XY: 0.000589 AC XY: 428 AN XY: 726112

African (AFR) AF: 0.0214 AC: 715 AN: 33454

American (AMR) AF: 0.00119 AC: 53 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111316

Other (OTH) AF: 0.00181 AC: 109 AN: 60306

GnomAD4 genome AF: 0.00623 AC: 949 AN: 152288 Hom.: 10 Cov.: 32 AF XY: 0.00612 AC XY: 456 AN XY: 74456

African (AFR) AF: 0.0215 AC: 894 AN: 41562

American (AMR) AF: 0.00229 AC: 35 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00232 Hom.: 7

Bravo AF: 0.00711

ESP6500AA AF: 0.0162 AC: 70

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.64
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.69
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.044
Sift	Benign	0.034	D
Sift4G	Uncertain	0.047	D
Polyphen		0.70	P
Vest4		0.26
MVP		0.51
MPC		0.41
ClinPred		0.041	T
GERP RS		1.6
Varity_R		0.065
gMVP		0.32
Mutation Taster		=97/3	polymorphism

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: rs35687686; hg19: chr1-7887234; COSMIC: COSV62705474;