rs730882149

Variant names:

• chr15-71811507-GC-AGTGTGCCTCCAGTGCCTCGCTCCA
• rs730882149
• NM_014249.4:c.143_144delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_014249.4(NR2E3):​c.143_144delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA​(p.Arg48GlnfsTer66) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48C) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR2E3 NM_014249.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.81
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-71811507-GC-AGTGTGCCTCCAGTGCCTCGCTCCA is Pathogenic according to our data. Variant chr15-71811507-GC-AGTGTGCCTCCAGTGCCTCGCTCCA is described in ClinVar as Pathogenic. ClinVar VariationId is 183143.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.143_144delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA	p.Arg48GlnfsTer66	frameshift_variant, missense_variant	Exon 2 of 8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.143_144delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA	p.Arg48GlnfsTer66	frameshift_variant, 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.143_144delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA	p.Arg48GlnfsTer66	frameshift_variant, missense_variant	Exon 2 of 8	1	NM_014249.4	ENSP00000482504.1
NR2E3	ENST00000621098.1	c.143_144delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA	p.Arg48GlnfsTer66	frameshift_variant, missense_variant	Exon 2 of 7	1		ENSP00000479962.1
NR2E3	ENST00000621736.4	c.-122_-121delGCinsAGTGTGCCTCCAGTGCCTCGCTCCA		5_prime_UTR_variant	Exon 4 of 10	2		ENSP00000479254.1

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Pathogenic:1

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Goldmann-Favre syndrome Pathogenic:1

Jul 16, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

Retinitis pigmentosa 37 Pathogenic:1

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

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

Other links and lift over

dbSNP: rs730882149; hg19: chr15-72103847;