chr1-7809900-A-G

Variant names:

• chr1-7809900-A-G
• rs139315125
• NM_001377275.1:c.1250A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001377275.1(PER3):​c.1250A>G​(p.His417Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,613,976 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 2.88
• Publications: 25 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: Likely_benign. The variant received -4 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	NM_001377275.1	MANE Select	c.1250A>G	p.His417Arg	missense	Exon 12 of 22	NP_001364204.1
	PER3	NM_001289862.2		c.1250A>G	p.His417Arg	missense	Exon 12 of 22	NP_001276791.1
	PER3	NM_001438696.1		c.1247A>G	p.His416Arg	missense	Exon 12 of 22	NP_001425625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.1250A>G	p.His417Arg	missense	Exon 12 of 22	ENSP00000366755.3
	PER3	ENST00000361923.2	TSL:1	c.1247A>G	p.His416Arg	missense	Exon 11 of 21	ENSP00000355031.2
	PER3	ENST00000614998.4	TSL:1	c.1250A>G	p.His417Arg	missense	Exon 12 of 23	ENSP00000479223.1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152224 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: 0.000955

GnomAD2 exomes AF: 0.00563 AC: 1410 AN: 250526 AF XY: 0.00568

Gnomad AFR exome AF: 0.000680

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0289

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00494 AC: 7214 AN: 1461634 Hom.: 44 Cov.: 35 AF XY: 0.00496 AC XY: 3604 AN XY: 727122

African (AFR) AF: 0.000418 AC: 14 AN: 33470

American (AMR) AF: 0.000873 AC: 39 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26124

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

South Asian (SAS) AF: 0.00201 AC: 173 AN: 86230

European-Finnish (FIN) AF: 0.0266 AC: 1419 AN: 53394

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.00477 AC: 5303 AN: 1111880

Other (OTH) AF: 0.00421 AC: 254 AN: 60386

GnomAD4 genome AF: 0.00495 AC: 754 AN: 152342 Hom.: 3 Cov.: 34 AF XY: 0.00570 AC XY: 425 AN XY: 74500

African (AFR) AF: 0.000577 AC: 24 AN: 41588

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: 5188

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0290 AC: 308 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00569 AC: 387 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00441 Hom.: 10

Bravo AF: 0.00267

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00442 AC: 38

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 as Germline

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	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.14
Sift	Benign	0.28	T
Sift4G	Benign	0.085	T
Polyphen		0.29	B
Vest4		0.15
MVP		0.55
MPC		0.10
ClinPred		0.089	T
GERP RS		2.1
Varity_R		0.22
gMVP		0.74
Mutation Taster		=84/16	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139315125; hg19: chr1-7869960; COSMIC: COSV100728538; COSMIC: COSV100728538;