dbSNP rs766096417: NR2E3:p.Arg104Gln (chr15-71811831-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PM1PM5PP3_ModeratePP5_Very_Strong

The NM_014249.4(NR2E3):c.311G>A(p.Arg104Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,551,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 10/16 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001203262: Experimental studies have shown that this missense change affects NR2E3 function (PMID:19898638).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.81

Publications

12 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: Labcorp Genetics (formerly Invitae), G2P
enhanced S-cone syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_014249.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001203262: Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_014249.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-71811830-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 846973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 15-71811831-G-A is Pathogenic according to our data. Variant chr15-71811831-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438228.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.311G>A	p.Arg104Gln	missense	Exon 3 of 8	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.311G>A	p.Arg104Gln	missense	Exon 3 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.311G>A	p.Arg104Gln	missense	Exon 3 of 8	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1	TSL:1	c.311G>A	p.Arg104Gln	missense	Exon 3 of 7	ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4	TSL:2	c.47G>A	p.Arg16Gln	missense	Exon 5 of 10	ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000196

AC:

AN:

152762

AF XY:

0.0000369

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000171

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1399098

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

690124

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31600

American (AMR)

AF:

0.00

AC:

AN:

35708

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25166

East Asian (EAS)

AF:

0.000112

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

1079032

Other (OTH)

AF:

0.0000172

AC:

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.0000340

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Retinal dystrophy (3)

Enhanced S-cone syndrome (2)

Retinitis pigmentosa (2)

Retinitis pigmentosa 37 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

4.2

PhyloP100

9.8

PrimateAI

Pathogenic

0.88

Sift4G

Uncertain

0.0040

Varity_R

0.86

gMVP

0.90

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over