17-8142829-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002616.3(PER1):c.3079G>A(p.Val1027Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,598,706 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1027D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (31 hom.)
• Consequence: PER1 NM_002616.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.790

Genes affected

PER1 (HGNC:8845): (period circadian regulator 1) 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 may increase the risk of getting certain cancers. Alternative splicing has been observed in this gene; however, these variants have not been fully described. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020554662).
• BP6: Variant 17-8142829-C-T is Benign according to our data. Variant chr17-8142829-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 718368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER1	NM_002616.3	c.3079G>A	p.Val1027Ile	missense_variant	20/23	ENST00000317276.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER1	ENST00000317276.9	c.3079G>A	p.Val1027Ile	missense_variant	20/23	1	NM_002616.3	P1
PER1	ENST00000581082.5	c.3010G>A	p.Val1004Ile	missense_variant	19/22	5
PER1	ENST00000579098.1	n.86G>A		non_coding_transcript_exon_variant	2/2	2
PER1	ENST00000582719.5	c.2468G>A	p.Gly823Asp	missense_variant, NMD_transcript_variant	19/22	5

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 152082 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00397 AC: 877 AN: 220678 Hom.: 8 AF XY: 0.00399 AC XY: 481 AN XY: 120546

Gnomad AFR exome AF: 0.000848

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000757

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00497

GnomAD4 exome AF: 0.00420 AC: 6078 AN: 1446506 Hom.: 31 Cov.: 34 AF XY: 0.00421 AC XY: 3025 AN XY: 719152

Gnomad4 AFR exome AF: 0.000451

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.000540

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000821

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.00424

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152200 Hom.: 5 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74408

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00270 Hom.: 20

Bravo AF: 0.00201

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00373 AC: 32

ExAC AF: 0.00388 AC: 469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	May 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PER1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.51	N;.
REVEL	Benign	0.081
Sift	Benign	0.35	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.0	B;.
Vest4		0.059
MVP		0.068
MPC		0.42
ClinPred		0.014	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038

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: rs12937495; hg19: chr17-8046147; COSMIC: COSV100424145; COSMIC: COSV100424145;