rs150812083

chr1-7809893-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 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. 2/2 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:1
• Conservation: PhyloP100: 6.94

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]

LOC124903833 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP5: Variant 1-7809893-C-G is Pathogenic according to our data. Variant chr1-7809893-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242410.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009827554).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 753 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER3	NM_001377275.1	c.1243C>G	p.Pro415Ala	missense_variant, splice_region_variant	12/22	ENST00000377532.8
LOC124903833	XR_007065450.1	n.1784G>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.1243C>G	p.Pro415Ala	missense_variant, splice_region_variant	12/22	1	NM_001377275.1	A2

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

GnomAD3 exomes AF: 0.00562 AC: 1406 AN: 249982 Hom.: 12 AF XY: 0.00568 AC XY: 768 AN XY: 135180

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 SAS exome AF: 0.00236

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

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: 0.00475

Gnomad4 OTH exome AF: 0.00421

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

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.00569

Gnomad4 OTH AF: 0.000946

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

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, PP4, BP4, BS1:Supporting -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs150812083; hg19: chr1-7869953; COSMIC: COSV100728537; COSMIC: COSV100728537;