chr1-7793969-A-C

Position:

• chr1-7793969-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001377275.1(PER3):​c.605A>C​(p.Tyr202Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.517

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER3	NM_001377275.1	c.605A>C	p.Tyr202Ser	missense_variant	6/22	ENST00000377532.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER3	ENST00000377532.8	c.605A>C	p.Tyr202Ser	missense_variant	6/22	1	NM_001377275.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.602A>C (p.Y201S) alteration is located in exon 5 (coding exon 5) of the PER3 gene. This alteration results from a A to C substitution at nucleotide position 602, causing the tyrosine (Y) at amino acid position 201 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.028	.;.;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.67	T;T;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	.;.;.;.;L
MutationTaster	Benign	0.53	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.4	D;.;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.37	T;.;.;T;D
Sift4G	Benign	0.41	T;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;D
Vest4		0.57
MutPred		0.45		Gain of disorder (P = 0.0486);.;.;.;Gain of disorder (P = 0.0486);
MVP		0.61
MPC		0.47
ClinPred		0.89	D
GERP RS		0.86
Varity_R		0.12
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-7854029;