chr15-71813408-C-A

Position:

chr15-71813408-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_014249.4(NR2E3):c.767C>A(p.Ala256Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,611,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 9/14 in silico tools predict a damaging 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. A256V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain NR LBD (size 241) in uniprot entity NR2E3_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_014249.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-71813408-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 15-71813408-C-A is Pathogenic according to our data. Variant chr15-71813408-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71813408-C-A is described in Lovd as [Likely_pathogenic]. Variant chr15-71813408-C-A is described in Lovd as [Pathogenic]. Variant chr15-71813408-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2E3	NM_014249.4 linkuse as main transcript	c.767C>A	p.Ala256Glu	missense_variant	6/8	ENST00000617575.5	NP_055064.1	Q9Y5X4-1
NR2E3	NM_016346.4 linkuse as main transcript	c.767C>A	p.Ala256Glu	missense_variant	6/7		NP_057430.1	Q9Y5X4-2F1D8Q9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NR2E3	ENST00000617575.5 linkuse as main transcript	c.767C>A	p.Ala256Glu	missense_variant	6/8	1	NM_014249.4	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1 linkuse as main transcript	c.767C>A	p.Ala256Glu	missense_variant	6/7	1		ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4 linkuse as main transcript	c.503C>A	p.Ala168Glu	missense_variant	8/10	2		ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000371

AC:

AN:

242284

Hom.:

AF XY:

0.0000380

AC XY:

AN XY:

131520

show subpopulations

Gnomad AFR exome

AF:

0.0000664

Gnomad AMR exome

AF:

0.0000882

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000460

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

249

AN:

1459192

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

113

AN XY:

725564

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000675

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000216

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 256 of the NR2E3 protein (p.Ala256Glu). This variant is present in population databases (rs377257254, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive NR2E3-related conditions (PMID: 12963616, 25079116). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NR2E3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638, 25703721, 28300834). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2024	Identified in patients with features of an NR2E3-related retinal dystrophy in published literature (PMID: 25079116, 28041643, 15459973, 12963616); Published functional studies demonstrate impairment of protein localization, binding, and function (PMID: 19898638, 28300834); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19718767, 25703721, 25097241, 28300834, 15453866, 28041643, 15459973, 29343940, 12963616, 24425859, 16225923, 32679203, 31589614, Vafaeie[preprint], 38219857, 37510230, 32037395, 36460718, 31964843, 33513943, 25079116, 34906470, 19898638) -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 05, 2017	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Enhanced S-cone syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Retinitis pigmentosa 37

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The NR2E3 c.767C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. -

Goldmann-Favre syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 04, 2020

The p.Ala256Glu variant in NR2E3 has been reported in the compound heterozygous state 6 individuals with retinal disease (Sharon 2003 PMID:12963616, Hull 2014 PMID:25079116, Carss 2017 PMID: 28041643, Bryant 2018 PMID: 29343940). It has also been identified in 0.009% (3/34014) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID:438229). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Kanda 2009 PMID: 19898638, von Alpen 2015 PMID: 25703721). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Enhanced S-Cone syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Moderate, PP3. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Ala256Glu variant in NR2E3 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Benign

0.91

DEOGEN2

Pathogenic

0.92

.;D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.4

.;M;M

PrimateAI

Pathogenic

0.86

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.94

MVP

0.91

ClinPred

0.99

GERP RS

5.3

Varity_R

0.85

gMVP

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over