Genetic Variant NR1D2:p.Arg175Trp (chr3-23961982-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_005126.5(NR1D2):c.523C>T(p.Arg175Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

NR1D2
NM_005126.5 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.92

Publications

4 publications found

Variant links:

Genes affected

NR1D2 (HGNC:7963): (nuclear receptor subfamily 1 group D member 2) This gene encodes a member of the nuclear hormone receptor family, specifically the NR1 subfamily of receptors. The encoded protein functions as a transcriptional repressor and may play a role in circadian rhythms and carbohydrate and lipid metabolism. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]

NR1D2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 3-23961982-C-T is Pathogenic according to our data. Variant chr3-23961982-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 690345.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005126.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR1D2	NM_005126.5	MANE Select	c.523C>T	p.Arg175Trp	missense	Exon 5 of 8	NP_005117.3
NR1D2	NM_001145425.2		c.298C>T	p.Arg100Trp	missense	Exon 5 of 8	NP_001138897.1	B4DXD3
NR1D2	NR_110524.2		n.816C>T		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR1D2	ENST00000312521.9	TSL:1 MANE Select	c.523C>T	p.Arg175Trp	missense	Exon 5 of 8	ENSP00000310006.3	Q14995
NR1D2	ENST00000383773.8	TSL:1	n.523C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000373283.3	Q6NSM0
NR1D2	ENST00000947380.1		c.523C>T	p.Arg175Trp	missense	Exon 5 of 7	ENSP00000617439.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

238116

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial atrioventricular septal defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.0

PhyloP100

2.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.93

MutPred

0.65

Loss of disorder (P = 0.0149)

MVP

0.97

MPC

0.81

ClinPred

0.99

GERP RS

4.0

gMVP

0.82

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over