chr1-7785422-A-AT

Variant names:

• chr1-7785422-A-AT
• rs554573019
• NM_001377275.1:c.129-10dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001377275.1(PER3):​c.129-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,578,936 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: PER3 NM_001377275.1 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.347
• Publications: 0 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 -5 ACMG points.

• BP6: Variant 1-7785422-A-AT is Benign according to our data. Variant chr1-7785422-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 3034361.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 86 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.129-10dupT		intron	N/A	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.129-10dupT		intron	N/A	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.129-10dupT		intron	N/A	NP_001425625.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.129-19_129-18insT		intron	N/A	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.129-19_129-18insT		intron	N/A	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.129-19_129-18insT		intron	N/A	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes AF: 0.000567 AC: 86 AN: 151658 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000987

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000636 AC: 140 AN: 220170 AF XY: 0.000574

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000344

Gnomad ASJ exome AF: 0.000126

Gnomad EAS exome AF: 0.000121

Gnomad FIN exome AF: 0.000198

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.00124 AC: 1772 AN: 1427164 Hom.: 1 Cov.: 28 AF XY: 0.00118 AC XY: 837 AN XY: 710952

African (AFR) AF: 0.000430 AC: 14 AN: 32532

American (AMR) AF: 0.0000688 AC: 3 AN: 43606

Ashkenazi Jewish (ASJ) AF: 0.000157 AC: 4 AN: 25470

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39164

South Asian (SAS) AF: 0.000320 AC: 27 AN: 84436

European-Finnish (FIN) AF: 0.0000755 AC: 4 AN: 52988

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5674

European-Non Finnish (NFE) AF: 0.00154 AC: 1673 AN: 1084286

Other (OTH) AF: 0.000678 AC: 40 AN: 59008

GnomAD4 genome AF: 0.000567 AC: 86 AN: 151772 Hom.: 0 Cov.: 32 AF XY: 0.000580 AC XY: 43 AN XY: 74154

African (AFR) AF: 0.000266 AC: 11 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4794

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10532

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

European-Non Finnish (NFE) AF: 0.000987 AC: 67 AN: 67876

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000567

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PER3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
BranchPoint Hunter		1.0
Mutation Taster		=100/0	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: rs554573019; hg19: chr1-7845482;