15-71811831-G-T

Variant names:

• chr15-71811831-G-T
• rs766096417
• NM_014249.4:c.311G>T
• NR2E3 p.Arg104Leu

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_014249.4(NR2E3):​c.311G>T​(p.Arg104Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 10/16 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.81
• 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: Labcorp Genetics (formerly Invitae), G2P
• enhanced S-cone syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr15-71811830-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 846973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	NM_014249.4	MANE Select	c.311G>T	p.Arg104Leu	missense	Exon 3 of 8	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.311G>T	p.Arg104Leu	missense	Exon 3 of 7	NP_057430.1	F1D8Q9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E3	ENST00000617575.5	TSL:1 MANE Select	c.311G>T	p.Arg104Leu	missense	Exon 3 of 8	ENSP00000482504.1	Q9Y5X4-1
	NR2E3	ENST00000621098.1	TSL:1	c.311G>T	p.Arg104Leu	missense	Exon 3 of 7	ENSP00000479962.1	Q9Y5X4-2
	NR2E3	ENST00000621736.4	TSL:2	c.47G>T	p.Arg16Leu	missense	Exon 5 of 10	ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399098 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690124

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.00 AC: 0 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079032

Other (OTH) AF: 0.00 AC: 0 AN: 58008

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	33
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.91	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.97
gMVP		0.92

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766096417;

hg19: chr15-72104171;