rs146403122

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_014249.4(NR2E3):c.361G>A(p.Glu121Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,550,932 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E121E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 51 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.64

Publications

14 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: Labcorp Genetics (formerly Invitae), G2P, 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_014249.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008704543).

BP6

Variant 15-71811966-G-A is Benign according to our data. Variant chr15-71811966-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00231 (352/152318) while in subpopulation EAS AF = 0.0444 (230/5176). AF 95% confidence interval is 0.0397. There are 4 homozygotes in GnomAd4. There are 201 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4 link	c.361G>A	p.Glu121Lys	missense_variant	Exon 4 of 8	ENST00000617575.5	NP_055064.1	Q9Y5X4-1
NR2E3	NM_016346.4 link	c.361G>A	p.Glu121Lys	missense_variant	Exon 4 of 7		NP_057430.1	Q9Y5X4-2F1D8Q9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR2E3	ENST00000617575.5 link	c.361G>A	p.Glu121Lys	missense_variant	Exon 4 of 8	1	NM_014249.4	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1 link	c.361G>A	p.Glu121Lys	missense_variant	Exon 4 of 7	1		ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4 link	c.97G>A	p.Glu33Lys	missense_variant	Exon 6 of 10	2		ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

352

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0443

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00432

AC:

665

AN:

153770

AF XY:

0.00425

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.000353

Gnomad EAS exome

AF:

0.0495

Gnomad FIN exome

AF:

0.00503

Gnomad NFE exome

AF:

0.000433

Gnomad OTH exome

AF:

0.00276

GnomAD4 exome

AF:

0.00172

AC:

2401

AN:

1398614

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1119

AN XY:

689944

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31596

American (AMR)

AF:

0.0000559

AC:

AN:

35766

Ashkenazi Jewish (ASJ)

AF:

0.000556

AC:

AN:

25172

East Asian (EAS)

AF:

0.0407

AC:

1454

AN:

35728

South Asian (SAS)

AF:

0.000757

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00659

AC:

317

AN:

48128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.000406

AC:

438

AN:

1079276

Other (OTH)

AF:

0.00196

AC:

114

AN:

58024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

162

325

487

650

812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00231

AC:

352

AN:

152318

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

201

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41570

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0444

AC:

230

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00480

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00122

Hom.:

Bravo

AF:

0.00218

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000124

AC:

ExAC

AF:

0.00207

AC:

212

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NR2E3: BS1, BS2 -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37

Benign:2

May 31, 2017

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Enhanced S-cone syndrome

Benign:1

Apr 17, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Benign

0.80

DEOGEN2

Uncertain

0.60

.;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.5

.;M;M

PhyloP100

6.6

PrimateAI

Uncertain

0.78

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.92

MVP

0.69

ClinPred

0.24

GERP RS

4.5

Varity_R

0.29

gMVP

0.68

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over