1-7827433-T-C

Variant names:

• chr1-7827433-T-C
• rs228696
• NM_001377275.1:c.2504T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377275.1(PER3):​c.2504T>C​(p.Leu835Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,614,184 control chromosomes in the GnomAD database, including 745,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.97 (71045 hom., cov: 34)
  • Exomes 𝑓: 0.96 (674908 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.951
• Publications: 33 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

ENSG00000236266 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2495445E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PER3	NM_001377275.1	c.2504T>C	p.Leu835Pro	missense_variant	Exon 18 of 22	ENST00000377532.8	NP_001364204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PER3	ENST00000377532.8	c.2504T>C	p.Leu835Pro	missense_variant	Exon 18 of 22	1	NM_001377275.1	ENSP00000366755.3

Frequencies

GnomAD3 genomes AF: 0.966 AC: 146998 AN: 152236 Hom.: 70988 Cov.: 34

Gnomad AFR AF: 0.972

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.976

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.979

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.957

Gnomad OTH AF: 0.964

GnomAD2 exomes AF: 0.970 AC: 243853 AN: 251466 AF XY: 0.969

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 0.974

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.968

Gnomad NFE exome AF: 0.957

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.961 AC: 1404595 AN: 1461830 Hom.: 674908 Cov.: 62 AF XY: 0.961 AC XY: 699045 AN XY: 727224

African (AFR) AF: 0.974 AC: 32591 AN: 33478

American (AMR) AF: 0.984 AC: 44008 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.975 AC: 25487 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39689 AN: 39698

South Asian (SAS) AF: 0.977 AC: 84239 AN: 86258

European-Finnish (FIN) AF: 0.966 AC: 51590 AN: 53392

Middle Eastern (MID) AF: 0.974 AC: 5616 AN: 5768

European-Non Finnish (NFE) AF: 0.956 AC: 1063247 AN: 1111984

Other (OTH) AF: 0.963 AC: 58128 AN: 60392

GnomAD4 genome AF: 0.966 AC: 147114 AN: 152354 Hom.: 71045 Cov.: 34 AF XY: 0.966 AC XY: 71977 AN XY: 74492

African (AFR) AF: 0.972 AC: 40435 AN: 41580

American (AMR) AF: 0.971 AC: 14863 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 3389 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 0.979 AC: 4726 AN: 4828

European-Finnish (FIN) AF: 0.968 AC: 10280 AN: 10622

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.957 AC: 65105 AN: 68042

Other (OTH) AF: 0.964 AC: 2037 AN: 2112

Alfa AF: 0.961 Hom.: 152864

Bravo AF: 0.966

TwinsUK AF: 0.952 AC: 3531

ALSPAC AF: 0.959 AC: 3695

ESP6500AA AF: 0.973 AC: 4288

ESP6500EA AF: 0.955 AC: 8211

ExAC AF: 0.969 AC: 117630

Asia WGS AF: 0.986 AC: 3429 AN: 3478

EpiCase AF: 0.955

EpiControl AF: 0.957

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.6
DANN	Benign	0.45
DEOGEN2	Benign	0.013	.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.16	T;T;.;T
MetaRNN	Benign	0.0000012	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.4	.;.;.;N
PhyloP100		0.95
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.6	.;.;N;N
REVEL	Benign	0.047
Sift	Benign	0.50	.;.;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.090
MPC		0.14
ClinPred		0.0088	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.028
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs228696; hg19: chr1-7887493; COSMIC: COSV100728488; COSMIC: COSV100728488;