15-71811530-G-C

Variant names:

• chr15-71811530-G-C
• rs121912631
• NM_014249.4:c.166G>C

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_014249.4(NR2E3):​c.166G>C​(p.Gly56Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G56G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.66
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 24 ACMG points.

• PS1: Transcript NM_014249.4 (NR2E3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 5533
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_014249.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 15-71811530-G-C is Pathogenic according to our data. Variant chr15-71811530-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1076269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4	c.166G>C	p.Gly56Arg	missense_variant	Exon 2 of 8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.166G>C	p.Gly56Arg	missense_variant	Exon 2 of 7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5	c.166G>C	p.Gly56Arg	missense_variant	Exon 2 of 8	1	NM_014249.4	ENSP00000482504.1
NR2E3	ENST00000621098.1	c.166G>C	p.Gly56Arg	missense_variant	Exon 2 of 7	1		ENSP00000479962.1
NR2E3	ENST00000621736.4	c.-99G>C		5_prime_UTR_variant	Exon 4 of 10	2		ENSP00000479254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jan 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect NR2E3 protein function (PMID: 19823680, 19006237). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 24938718, 17564971, 26910043, 19006237). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 56 of the NR2E3 protein (p.Gly56Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Retinal dystrophy Pathogenic:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		9.7
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.95		Loss of glycosylation at S55 (P = 0.08);Loss of glycosylation at S55 (P = 0.08);
MVP		0.84
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.65
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912631; hg19: chr15-72103870;