rs2723341

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_014249.4(NR2E3):c.119-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00066 in 1,555,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

NR2E3
NM_014249.4 splice_acceptor, intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:38

Conservation

PhyloP100: 4.05

Publications

35 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 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 15-71811481-A-C is Pathogenic according to our data. Variant chr15-71811481-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 191059.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.119-2A>C		splice_acceptor intron	N/A	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.119-2A>C		splice_acceptor intron	N/A	NP_057430.1	F1D8Q9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NR2E3	ENST00000617575.5	TSL:1 MANE Select	c.119-2A>C	splice_acceptor intron	N/A	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1	TSL:1	c.119-2A>C	splice_acceptor intron	N/A	ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4	TSL:2	c.-146-2A>C	splice_acceptor intron	N/A	ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.000507

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000927

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000526

AC:

AN:

161472

AF XY:

0.000511

show subpopulations

Gnomad AFR exome

AF:

0.000367

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00116

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000618

Gnomad NFE exome

AF:

0.000990

Gnomad OTH exome

AF:

0.000441

GnomAD4 exome

AF:

0.000676

AC:

949

AN:

1402938

Hom.:

Cov.:

AF XY:

0.000683

AC XY:

473

AN XY:

692406

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

31742

American (AMR)

AF:

0.000111

AC:

AN:

35974

Ashkenazi Jewish (ASJ)

AF:

0.00131

AC:

AN:

25226

East Asian (EAS)

AF:

0.00

AC:

AN:

35970

South Asian (SAS)

AF:

0.0000629

AC:

AN:

79476

European-Finnish (FIN)

AF:

0.0000404

AC:

AN:

49494

Middle Eastern (MID)

AF:

0.000610

AC:

AN:

4920

European-Non Finnish (NFE)

AF:

0.000791

AC:

856

AN:

1081972

Other (OTH)

AF:

0.000688

AC:

AN:

58164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000506

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41518

American (AMR)

AF:

0.000131

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000927

AC:

AN:

67970

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000575

Hom.:

Bravo

AF:

0.000468

ExAC

AF:

0.000192

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (10)

Enhanced S-cone syndrome (6)

Retinitis pigmentosa 37 (5)

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 (4)

Retinal dystrophy (3)

Retinitis pigmentosa (3)

Color vision defect;C0271385:Horizontal nystagmus;C0854723:Retinal dystrophy;C3665347:Visual impairment (1)

Cone-rod dystrophy (1)

Goldmann-Favre syndrome (1)

Inborn genetic diseases (1)

not specified (1)

NR2E3-related disorder (1)

Ocular albinism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Benign

0.94

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.76

PhyloP100

4.1

GERP RS

3.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.95

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