rs11351249

chr15-71813588-AC-Achr15-71813588-AC-ACC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 10P and 8B. PVS1 PM2 BP6_Very_Strong

The NM_014249.4(NR2E3):c.951del(p.Thr318ArgfsTer6) 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D316D) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 1.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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
• BP6: Variant 15-71813588-AC-A is Benign according to our data. Variant chr15-71813588-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 445726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2E3	NM_014249.4	c.951del	p.Thr318ArgfsTer6	frameshift_variant	6/8	ENST00000617575.5
NR2E3	NM_016346.4	c.951del	p.Thr318ArgfsTer6	frameshift_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2E3	ENST00000617575.5	c.951del	p.Thr318ArgfsTer6	frameshift_variant	6/8	1	NM_014249.4	P1
NR2E3	ENST00000621098.1	c.951del	p.Thr318ArgfsTer6	frameshift_variant	6/7	1
NR2E3	ENST00000621736.4	c.687del	p.Thr230ArgfsTer6	frameshift_variant	8/10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Enhanced S-cone syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Autosomal recessive retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Oct 26, 2012

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 04, 2017

- -

Retinitis pigmentosa 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs11351249; hg19: chr15-72105928;