1-7827433-T-C

Position:

• chr1-7827433-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PER3	NM_001377275.1	c.2504T>C	p.Leu835Pro	missense_variant	18/22	ENST00000377532.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.2504T>C	p.Leu835Pro	missense_variant	18/22	1	NM_001377275.1	A2
PER3	ENST00000361923.2	c.2480T>C	p.Leu827Pro	missense_variant	17/21	1		P2
PER3	ENST00000614998.4	c.2504T>C	p.Leu835Pro	missense_variant	18/23	1		A2
PER3	ENST00000613533.4	c.2504T>C	p.Leu835Pro	missense_variant	18/22	5		A2

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

GnomAD3 exomes AF: 0.970 AC: 243853 AN: 251466 Hom.: 118264 AF XY: 0.969 AC XY: 131693 AN XY: 135914

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 SAS exome AF: 0.978

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

Gnomad4 AFR exome AF: 0.974

Gnomad4 AMR exome AF: 0.984

Gnomad4 ASJ exome AF: 0.975

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.977

Gnomad4 FIN exome AF: 0.966

Gnomad4 NFE exome AF: 0.956

Gnomad4 OTH exome AF: 0.963

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

Gnomad4 AFR AF: 0.972

Gnomad4 AMR AF: 0.971

Gnomad4 ASJ AF: 0.976

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.979

Gnomad4 FIN AF: 0.968

Gnomad4 NFE AF: 0.957

Gnomad4 OTH AF: 0.964

Alfa AF: 0.960 Hom.: 109951

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
MutationTaster	Benign	1.0	P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs228696; hg19: chr1-7887493;