rs28937873

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_014249.4(NR2E3):c.932G>A(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R311W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28

Conservation

PhyloP100: 3.96

Publications

64 publications found

Variant links:

Genes affected

NR2E3 (HGNC:7974): (nuclear receptor subfamily 2 group E member 3) This protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as in maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding. This gene encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. Defects in this gene are a cause of enhanced S cone syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

NR2E3 Gene-Disease associations (from GenCC):

retinitis pigmentosa 37
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
enhanced S-cone syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Goldmann-Favre syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NR2E3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_014249.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-71813572-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422071.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-71813573-G-A is Pathogenic according to our data. Variant chr15-71813573-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	NM_014249.4	MANE Select	c.932G>A	p.Arg311Gln	missense	Exon 6 of 8	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.932G>A	p.Arg311Gln	missense	Exon 6 of 7	NP_057430.1	F1D8Q9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR2E3	ENST00000617575.5	TSL:1 MANE Select	c.932G>A	p.Arg311Gln	missense	Exon 6 of 8	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1	TSL:1	c.932G>A	p.Arg311Gln	missense	Exon 6 of 7	ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4	TSL:2	c.668G>A	p.Arg223Gln	missense	Exon 8 of 10	ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000395

AC:

AN:

222622

AF XY:

0.000404

show subpopulations

Gnomad AFR exome

AF:

0.0000723

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00475

Gnomad EAS exome

AF:

0.0000598

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000157

Gnomad OTH exome

AF:

0.000879

GnomAD4 exome

AF:

0.000183

AC:

267

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000716

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

106

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000908

AC:

101

AN:

1111846

Other (OTH)

AF:

0.000364

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000328

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41574

American (AMR)

AF:

0.00176

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000468

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000360

AC:

ExAC

AF:

0.000291

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Enhanced S-cone syndrome (8)

not provided (6)

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 (3)

Retinitis pigmentosa 37 (3)

Goldmann-Favre syndrome (2)

Retinal dystrophy (2)

Autosomal recessive retinitis pigmentosa (1)

Enhanced S-cone syndrome;CN239387:NR2E3-related disorder (1)

NR2E3-related disorder (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Uncertain

0.74

Eigen

Benign

0.059

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

PhyloP100

4.0

PrimateAI

Benign

0.39

Sift4G

Benign

0.11

Polyphen

0.63

Vest4

0.71

MVP

0.62

ClinPred

0.92

GERP RS

3.3

Varity_R

0.55

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.69

Position offset: 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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over