1-7784970-C-G

Variant names:

• chr1-7784970-C-G
• rs767862865
• NM_001377275.1:c.93C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001289864.3(PER3):​c.-926C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,558,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PER3 NM_001289864.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.605
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048118442).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289864.3. 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.93C>G	p.Phe31Leu	missense	Exon 2 of 22	NP_001364204.1	P56645-2
	PER3	NM_001289864.3		c.-926C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001276793.1
	PER3	NM_001289862.2		c.93C>G	p.Phe31Leu	missense	Exon 2 of 22	NP_001276791.1	P56645-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.93C>G	p.Phe31Leu	missense	Exon 2 of 22	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.93C>G	p.Phe31Leu	missense	Exon 1 of 21	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.93C>G	p.Phe31Leu	missense	Exon 2 of 23	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406140 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699272

African (AFR) AF: 0.00 AC: 0 AN: 28770

American (AMR) AF: 0.00 AC: 0 AN: 31342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35070

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092824

Other (OTH) AF: 0.00 AC: 0 AN: 57918

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.60
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.035
Sift	Benign	0.41	T
Sift4G	Benign	0.40	T
Polyphen		0.056	B
Vest4		0.093
MutPred		0.14		Gain of MoRF binding (P = 0.1442)
MVP		0.24
MPC		0.10
ClinPred		0.032	T
GERP RS		2.3
PromoterAI		0.029	Neutral
Varity_R		0.051
gMVP		0.076
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: rs767862865; hg19: chr1-7845030;