rs730882149

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_014249.4(NR2E3):​c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA​(p.Arg48GlnfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R48R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

NR2E3
NM_014249.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.81
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-71811507-GC-AGTGTGCCTCCAGTGCCTCGCTCCA is Pathogenic according to our data. Variant chr15-71811507-GC-AGTGTGCCTCCAGTGCCTCGCTCCA is described in ClinVar as [Pathogenic]. Clinvar id is 183143.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NR2E3NM_014249.4 linkuse as main transcriptc.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA p.Arg48GlnfsTer66 frameshift_variant 2/8 ENST00000617575.5
NR2E3NM_016346.4 linkuse as main transcriptc.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA p.Arg48GlnfsTer66 frameshift_variant 2/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NR2E3ENST00000617575.5 linkuse as main transcriptc.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA p.Arg48GlnfsTer66 frameshift_variant 2/81 NM_014249.4 P1Q9Y5X4-1
NR2E3ENST00000621098.1 linkuse as main transcriptc.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA p.Arg48GlnfsTer66 frameshift_variant 2/71 Q9Y5X4-2
NR2E3ENST00000621736.4 linkuse as main transcriptc.-122_-121delinsAGTGTGCCTCCAGTGCCTCGCTCCA 5_prime_UTR_variant 4/102

Frequencies

GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinitis pigmentosa 37 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2012- -
Goldmann-Favre syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 16, 2020The c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48GlnfsX66) variant in NR2E3 has been reported in the homozygous state in 1 consanguineous individual with cone-rod dystrophy and night blindness and segregated with disease in 1 affected sibling (Kannibiran 2012 PMID: 22605927). It was absent from large population studies, though the ability to detect variants of this size may be diminished. This variant is a deletion of two nucleotides and an insertion of 25 nucleotides and is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 48 and leads to a premature termination codon 66 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NR2E3 gene is an established disease mechanism in autosomal recessive enhanced S-cone syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive enhanced S-cone syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs730882149; hg19: chr15-72103847; API