rs10462021

Variant names:

• chr1-7837073-A-C
• rs10462021
• NM_001377275.1:c.3473A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-7837073-A-C
• chr1-7837073-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377275.1(PER3):​c.3473A>C​(p.His1158Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PER3 NM_001377275.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030650675).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377275.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	NM_001377275.1	MANE Select	c.3473A>C	p.His1158Pro	missense	Exon 21 of 22	NP_001364204.1	P56645-2
	PER3	NM_001289862.2		c.3473A>C	p.His1158Pro	missense	Exon 21 of 22	NP_001276791.1	P56645-2
	PER3	NM_001438696.1		c.3470A>C	p.His1157Pro	missense	Exon 21 of 22	NP_001425625.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PER3	ENST00000377532.8	TSL:1 MANE Select	c.3473A>C	p.His1158Pro	missense	Exon 21 of 22	ENSP00000366755.3	P56645-2
	PER3	ENST00000361923.2	TSL:1	c.3446A>C	p.His1149Pro	missense	Exon 20 of 21	ENSP00000355031.2	P56645-1
	PER3	ENST00000614998.4	TSL:1	c.3416A>C	p.His1139Pro	missense	Exon 22 of 23	ENSP00000479223.1	A0A087WV69

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461364 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726996

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111588

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.32
DANN	Benign	0.64
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.017
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.019
Sift	Benign	0.20	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.15		Gain of glycosylation at H1149 (P = 0.012)
MVP		0.12
MPC		0.15
ClinPred		0.052	T
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.16
Mutation Taster		=97/3	polymorphism

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: rs10462021; hg19: chr1-7897133;