NM_014249.4:c.926G>T

Variant names:

• chr15-71813567-G-T
• rs761628767
• NM_014249.4:c.926G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_014249.4(NR2E3):​c.926G>T​(p.Arg309Leu) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R309G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.91

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain NR LBD (size 241) in uniprot entity NR2E3_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_014249.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 15-71813567-G-T is Pathogenic according to our data. Variant chr15-71813567-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191062.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-71813567-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4	c.926G>T	p.Arg309Leu	missense_variant	Exon 6 of 8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.926G>T	p.Arg309Leu	missense_variant	Exon 6 of 7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5	c.926G>T	p.Arg309Leu	missense_variant	Exon 6 of 8	1	NM_014249.4	ENSP00000482504.1
NR2E3	ENST00000621098.1	c.926G>T	p.Arg309Leu	missense_variant	Exon 6 of 7	1		ENSP00000479962.1
NR2E3	ENST00000621736.4	c.662G>T	p.Arg221Leu	missense_variant	Exon 8 of 10	2		ENSP00000479254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Enhanced S-cone syndrome Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Retinitis pigmentosa 37 Pathogenic:1

Apr 16, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Uncertain	26
DANN	Benign	0.87
DEOGEN2	Pathogenic	0.83	.;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.5	.;H;H
PrimateAI	Uncertain	0.63	T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.99
MutPred		0.68		.;Loss of MoRF binding (P = 0.0371);Loss of MoRF binding (P = 0.0371);
MVP		0.82
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.66

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

Other links and lift over

dbSNP: rs761628767; hg19: chr15-72105907;