NM_001377275.1:c.1243C>G

Variant names:

• chr1-7809893-C-G
• rs150812083
• NM_001377275.1:c.1243C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001377275.1(PER3):​c.1243C>G​(p.Pro415Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00493 in 1,613,532 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0049 (44 hom.)
• Consequence: PER3 NM_001377275.1 missense, splice_region
• Scores: Splicing: ADA: 0.8318
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 6.94
• Publications: 28 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

LOC124903833 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009827554).
• BS2: High AC in GnomAd4 at 754 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.1243C>G	p.Pro415Ala	missense splice_region	Exon 12 of 22	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.1243C>G	p.Pro415Ala	missense splice_region	Exon 12 of 22	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.1240C>G	p.Pro414Ala	missense splice_region	Exon 12 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.1243C>G	p.Pro415Ala	missense splice_region	Exon 12 of 22	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.1240C>G	p.Pro414Ala	missense splice_region	Exon 11 of 21	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.1243C>G	p.Pro415Ala	missense splice_region	Exon 12 of 23	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152226 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00569

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00562 AC: 1406 AN: 249982 AF XY: 0.00568

Gnomad AFR exome AF: 0.000680

Gnomad AMR exome AF: 0.000842

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0290

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00492 AC: 7194 AN: 1461188 Hom.: 44 Cov.: 35 AF XY: 0.00495 AC XY: 3598 AN XY: 726886

African (AFR) AF: 0.000418 AC: 14 AN: 33460

American (AMR) AF: 0.000873 AC: 39 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26096

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00201 AC: 173 AN: 86194

European-Finnish (FIN) AF: 0.0266 AC: 1420 AN: 53374

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5750

European-Non Finnish (NFE) AF: 0.00475 AC: 5282 AN: 1111602

Other (OTH) AF: 0.00421 AC: 254 AN: 60370

GnomAD4 genome AF: 0.00495 AC: 754 AN: 152344 Hom.: 3 Cov.: 34 AF XY: 0.00570 AC XY: 425 AN XY: 74498

African (AFR) AF: 0.000577 AC: 24 AN: 41580

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.0290 AC: 308 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00569 AC: 387 AN: 68042

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00467 Hom.: 2

Bravo AF: 0.00267

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00581 AC: 705

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Advanced sleep phase syndrome 3 (2)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.79
MPC		0.36
ClinPred		0.054	T
GERP RS		4.4
Varity_R		0.77
gMVP		0.65
Mutation Taster		=41/59	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.65
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: rs150812083; hg19: chr1-7869953; COSMIC: COSV100728537; COSMIC: COSV100728537;