chr1-7786810-G-A

Variant names:

• chr1-7786810-G-A
• rs200696656
• NM_001377275.1:c.364G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377275.1(PER3):​c.364G>A​(p.Ala122Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,603,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069787234).
• BS2: High AC in GnomAdExome4 at 43 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.364G>A	p.Ala122Thr	missense	Exon 4 of 22	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.364G>A	p.Ala122Thr	missense	Exon 4 of 22	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.364G>A	p.Ala122Thr	missense	Exon 4 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.364G>A	p.Ala122Thr	missense	Exon 4 of 22	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.364G>A	p.Ala122Thr	missense	Exon 3 of 21	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.364G>A	p.Ala122Thr	missense	Exon 4 of 23	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251308 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000296 AC: 43 AN: 1451808 Hom.: 0 Cov.: 27 AF XY: 0.0000332 AC XY: 24 AN XY: 722922

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.0000895 AC: 4 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1102832

Other (OTH) AF: 0.0000999 AC: 6 AN: 60078

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.14
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.43	N
PhyloP100		1.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.98	D
Vest4		0.16
MutPred		0.22		Gain of glycosylation at A122 (P = 0.032)
MVP		0.41
MPC		0.37
ClinPred		0.13	T
GERP RS		4.3
Varity_R		0.063
gMVP		0.18
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs200696656; hg19: chr1-7846870; COSMIC: COSV62707293; COSMIC: COSV62707293;