rs766096417

Positions:

chr15-71811831-G-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.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. 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. R104W) has been classified as 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:8

Conservation

PhyloP100: 9.81

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 zinc_finger_region NR C4-type (size 25) in uniprot entity NR2E3_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_014249.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-71811830-C-T is described in Lovd as [Pathogenic].

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 [Likely_pathogenic]. Clinvar id is 438228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811831-G-A is described in Lovd as [Pathogenic]. Variant chr15-71811831-G-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.311G>A	p.Arg104Gln	missense_variant	3/8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4 linkuse as main transcript	c.311G>A	p.Arg104Gln	missense_variant	3/7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5 linkuse as main transcript	c.311G>A	p.Arg104Gln	missense_variant	3/8	1	NM_014249.4	ENSP00000482504	P1	Q9Y5X4-1
NR2E3	ENST00000621098.1 linkuse as main transcript	c.311G>A	p.Arg104Gln	missense_variant	3/7	1		ENSP00000479962		Q9Y5X4-2
NR2E3	ENST00000621736.4 linkuse as main transcript	c.47G>A	p.Arg16Gln	missense_variant	5/10	2		ENSP00000479254

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

GnomAD3 exomes

AF:

0.0000196

AC:

AN:

152762

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

81292

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 SAS exome

AF:

0.0000439

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

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.000112

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000185

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000116

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 04, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 104 of the NR2E3 protein (p.Arg104Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal recessive enhanced S-cone syndrome (PMID: 16225923, 23374571, 27522502; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438228). 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). This variant disrupts the p.Arg104 amino acid residue in NR2E3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15459973, 18436841, 19823680, 19898638, 25079116; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -

Enhanced S-cone syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 15, 2024

- -

Retinitis pigmentosa 37

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 25, 2022

_x000D_This variant was identified as compound heterozygous with NM_014249.4:c.230G>A Criteria applied: PM3_VSTR, PS3_MOD, PM2_SUP -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Benign

0.92

DEOGEN2

Pathogenic

0.95

.;D;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

4.2

.;H;H

PrimateAI

Pathogenic

0.88

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.97

MVP

0.83

ClinPred

0.98

GERP RS

4.3

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

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