rs139315125

Positions:

• chr1-7809900-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 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:1
• Conservation: PhyloP100: 2.88

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP5: Variant 1-7809900-A-G is Pathogenic according to our data. Variant chr1-7809900-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242411.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr1-7809900-A-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd4 at 754 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PER3	NM_001377275.1	c.1250A>G	p.His417Arg	missense_variant	12/22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.1250A>G	p.His417Arg	missense_variant	12/22	1	NM_001377275.1	ENSP00000366755.3

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

GnomAD3 exomes AF: 0.00563 AC: 1410 AN: 250526 Hom.: 12 AF XY: 0.00568 AC XY: 770 AN XY: 135466

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 SAS exome AF: 0.00235

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

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.00477

Gnomad4 OTH exome AF: 0.00421

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

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.00569

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00450 Hom.: 4

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Advanced sleep phase syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Bioinformatics dept., Datar Cancer Genetics Limited, India

Jun 23, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

PER3: PS3:Moderate, BP4, BS1:Supporting -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T;T;.;T
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;.;.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.9	.;.;D;D
REVEL	Benign	0.14
Sift	Benign	0.28	.;.;T;T
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.29	B;.;B;D
Vest4		0.15
MVP		0.55
MPC		0.10
ClinPred		0.089	T
GERP RS		2.1
Varity_R		0.22
gMVP		0.74

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

Publications

LitVar

Other links and lift over

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