Variant 17-40095446-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021724.5(NR1D1):c.1246C>A(p.Leu416Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,524,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

NR1D1
NM_021724.5 missense, splice_region

Scores

Splicing: ADA: 0.9880

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Variant links:

Genes affected

NR1D1 (HGNC:7962): (nuclear receptor subfamily 1 group D member 1) This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

NR1D1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1D1	NM_021724.5 linkuse as main transcript	c.1246C>A	p.Leu416Met	missense_variant, splice_region_variant	5/8	ENST00000246672.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1D1	ENST00000246672.4 linkuse as main transcript	c.1246C>A	p.Leu416Met	missense_variant, splice_region_variant	5/8	1	NM_021724.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

184138

Hom.:

AF XY:

0.0000103

AC XY:

AN XY:

97084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000341

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000306

AC:

AN:

1372150

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

672808

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000356

Gnomad4 OTH exome

AF:

0.0000710

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000872

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2023

The c.1246C>A (p.L416M) alteration is located in exon 5 (coding exon 5) of the NR1D1 gene. This alteration results from a C to A substitution at nucleotide position 1246, causing the leucine (L) at amino acid position 416 to be replaced by a methionine (M). 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

Uncertain

0.48

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Uncertain

-0.030

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.42

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.85

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.60

Sift

Benign

0.047

Sift4G

Uncertain

0.049

Polyphen

1.0

Vest4

0.39

MutPred

0.60

Gain of catalytic residue at L416 (P = 0.0275);

MVP

0.68

MPC

0.29

ClinPred

0.67

GERP RS

4.0

Varity_R

0.16

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over