15-71811969-C-T

Position:

chr15-71811969-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The ENST00000617575.5(NR2E3):c.364C>T(p.Arg122Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,550,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R122H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NR2E3
ENST00000617575.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:2

Conservation

PhyloP100: 4.87

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 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in ENST00000617575.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

PP5

Variant 15-71811969-C-T is Pathogenic according to our data. Variant chr15-71811969-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811969-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-71811969-C-T 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.364C>T	p.Arg122Cys	missense_variant	4/8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4 linkuse as main transcript	c.364C>T	p.Arg122Cys	missense_variant	4/7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5 linkuse as main transcript	c.364C>T	p.Arg122Cys	missense_variant	4/8	1	NM_014249.4	ENSP00000482504	P1	Q9Y5X4-1
NR2E3	ENST00000621098.1 linkuse as main transcript	c.364C>T	p.Arg122Cys	missense_variant	4/7	1		ENSP00000479962		Q9Y5X4-2
NR2E3	ENST00000621736.4 linkuse as main transcript	c.100C>T	p.Arg34Cys	missense_variant	6/10	2		ENSP00000479254

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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:

0.0000260

AC:

AN:

153982

Hom.:

AF XY:

0.0000366

AC XY:

AN XY:

81994

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:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

1398730

Hom.:

Cov.:

AF XY:

0.0000217

AC XY:

AN XY:

690020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000195

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 19, 2019	- -

Enhanced S-cone syndrome

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	clinical testing	Natera, Inc.	Apr 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

NR2E3-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The NR2E3 c.364C>T variant is predicted to result in the amino acid substitution p.Arg122Cys. This variant has been reported in the homozygous state in two siblings with retinitis pigmentosa from a consanguineous family (Family RP670, Bocquet et al. 2013. PubMed ID: 24339724). This variant has also been reported in the homozygous and compound heterozygous states in additional unrelated individuals with retinal dystrophies (Murro et al. 2018. PubMed ID: 30324420; Patient K6189, Table S6, Oishi et al. 2014. PubMed ID: 25324289; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395). This variant is reported in 0.0081% of alleles in individuals of East Asian descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the NR2E3 protein (p.Arg122Cys). 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 NR2E3-related conditions (PMID: 24339724, 30324420, 32037395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143147). 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%. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Department of Ophthalmology and Visual Sciences Kyoto University

- -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Benign

0.82

DEOGEN2

Pathogenic

0.80

.;D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

-0.029

MutationAssessor

Uncertain

2.5

.;M;M

PrimateAI

Uncertain

0.69

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.94

MutPred

0.53

.;Loss of MoRF binding (P = 0.0371);Loss of MoRF binding (P = 0.0371);

MVP

0.76

ClinPred

0.91

GERP RS

4.5

Varity_R

0.26

gMVP

0.76

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