17-8142775-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002616.3(PER1):c.3133C>A(p.Leu1045Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,613,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PER1 NM_002616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.270

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058772624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PER1	NM_002616.3	c.3133C>A	p.Leu1045Ile	missense_variant	20/23	ENST00000317276.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PER1	ENST00000317276.9	c.3133C>A	p.Leu1045Ile	missense_variant	20/23	1	NM_002616.3	P1
PER1	ENST00000581082.5	c.3064C>A	p.Leu1022Ile	missense_variant	19/22	5
PER1	ENST00000579098.1	n.140C>A		non_coding_transcript_exon_variant	2/2	2
PER1	ENST00000582719.5	c.*47C>A		3_prime_UTR_variant, NMD_transcript_variant	19/22	5

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000241 AC: 60 AN: 248982 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 134940

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000947

Gnomad NFE exome AF: 0.000491

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000365 AC: 533 AN: 1461206 Hom.: 0 Cov.: 34 AF XY: 0.000377 AC XY: 274 AN XY: 726944

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.000451

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74352

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000353 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000327

EpiControl AF: 0.000178

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

Jan 23, 2023

The c.3133C>A (p.L1045I) alteration is located in exon 20 (coding exon 19) of the PER1 gene. This alteration results from a C to A substitution at nucleotide position 3133, causing the leucine (L) at amino acid position 1045 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.000051
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.71	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.084
Sift	Benign	0.16	T;.
Sift4G	Benign	0.30	T;T
Polyphen		0.99	D;.
Vest4		0.20
MVP		0.14
MPC		0.61
ClinPred		0.13	T
GERP RS		2.1
Varity_R		0.088

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: rs141346567; hg19: chr17-8046093;