dbSNP rs749336987: NR1D1:p.Arg407Pro (chr17-40095472-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_021724.5(NR1D1):c.1220G>C(p.Arg407Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000036 in 1,387,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R407Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

NR1D1
NM_021724.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.616

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2025303).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D1	NM_021724.5 link	c.1220G>C	p.Arg407Pro	missense_variant	Exon 5 of 8	ENST00000246672.4	NP_068370.1	P20393F1D8S3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1D1	ENST00000246672.4 link	c.1220G>C	p.Arg407Pro	missense_variant	Exon 5 of 8	1	NM_021724.5	ENSP00000246672.3		P20393

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000360

AC:

AN:

1387920

Hom.:

Cov.:

AF XY:

0.00000733

AC XY:

AN XY:

682316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31138

American (AMR)

AF:

0.00

AC:

AN:

34246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21150

East Asian (EAS)

AF:

0.00

AC:

AN:

38968

South Asian (SAS)

AF:

0.0000667

AC:

AN:

74938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4870

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074670

Other (OTH)

AF:

0.00

AC:

AN:

57112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.087

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.69

M_CAP

Benign

0.055

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.39

MutationAssessor

Benign

-0.65

PhyloP100

0.62

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.38

REVEL

Uncertain

0.51

Sift

Benign

0.20

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.49

MutPred

0.48

Gain of catalytic residue at P406 (P = 0.0164);

MVP

0.88

MPC

0.053

ClinPred

0.24

GERP RS

5.0

Varity_R

0.21

gMVP

0.51

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over