chr15-71813573-G-A

Variant names:

• chr15-71813573-G-A
• rs28937873
• NM_014249.4:c.932G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP3 PP5_Very_Strong

The NM_014249.4(NR2E3):​c.932G>A​(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006585781: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:19006237, 19898638).; SCV000966899: In vitro functional studies on p.Arg311Gln provide evidence of varying impacts on protein function, potentially resulting in abnormal binding or cellular localization (Escher 2009, Roduit 2009, Kanda 2009, Fradot 2007).; SCV000618198: Published functional studies demonstrate mislocalization of the expressed protein to the cytoplasm, reduced DNA binding, and decreased transcriptional activity (Kanda et al., 2009; Escher et al., 2009).; SCV001551078: Functional studies show some evidence of this variant impacting protein function. This variant is suspected to impair corepressor-binding in ESCS, reduce repression of cone promoters, hinder the ability of photoreceptor cell-specific nuclear receptor (PNR) to form stable dimers, mislocalize in the cytoplasm, have reduced binding and interactions compared to wild type proteins and demonstrates a variable reduction in NR2E3-mediated increase in transcriptional activity (Kanda_2009_PMID:19898638; Gerber_2000_PMID:11071390, Escher_2009_PMID:19006237).; SCV000393797: Gerber et al. (2000) expressed the p.Arg311Gln variant protein in HEK293T cells and found that it hinders the formation of stable dimers but did not significantly alter the in vitro DNA binding capacities or the ability of the protein to repress transcription.; SCV001572153: Based on this evidence we have classified this variant as Pathogenic. PS3 no". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R311W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 3.96
• Publications: 65 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: G2P, Labcorp Genetics (formerly Invitae), 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006585781: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19006237, 19898638).; SCV000966899: In vitro functional studies on p.Arg311Gln provide evidence of varying impacts on protein function, potentially resulting in abnormal binding or cellular localization (Escher 2009, Roduit 2009, Kanda 2009, Fradot 2007).; SCV000618198: Published functional studies demonstrate mislocalization of the expressed protein to the cytoplasm, reduced DNA binding, and decreased transcriptional activity (Kanda et al., 2009; Escher et al., 2009).; SCV001551078: Functional studies show some evidence of this variant impacting protein function. This variant is suspected to impair corepressor-binding in ESCS, reduce repression of cone promoters, hinder the ability of photoreceptor cell-specific nuclear receptor (PNR) to form stable dimers, mislocalize in the cytoplasm, have reduced binding and interactions compared to wild type proteins and demonstrates a variable reduction in NR2E3-mediated increase in transcriptional activity (Kanda_2009_PMID:19898638; Gerber_2000_PMID:11071390, Escher_2009_PMID:19006237).; SCV000393797: Gerber et al. (2000) expressed the p.Arg311Gln variant protein in HEK293T cells and found that it hinders the formation of stable dimers but did not significantly alter the in vitro DNA binding capacities or the ability of the protein to repress transcription.; SCV001572153: Based on this evidence we have classified this variant as Pathogenic. PS3 no
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_014249.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-71813572-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422071.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-71813573-G-A is Pathogenic according to our data. Variant chr15-71813573-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.932G>A	p.Arg311Gln	missense	Exon 6 of 8	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.932G>A	p.Arg311Gln	missense	Exon 6 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.932G>A	p.Arg311Gln	missense	Exon 6 of 8	ENSP00000482504.1	Q9Y5X4-1
	NR2E3	ENST00000621098.1	TSL:1	c.932G>A	p.Arg311Gln	missense	Exon 6 of 7	ENSP00000479962.1	Q9Y5X4-2
	NR2E3	ENST00000621736.4	TSL:2	c.668G>A	p.Arg223Gln	missense	Exon 8 of 10	ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000395 AC: 88 AN: 222622 AF XY: 0.000404

Gnomad AFR exome AF: 0.0000723

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00475

Gnomad EAS exome AF: 0.0000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.000879

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461598 Hom.: 1 Cov.: 32 AF XY: 0.000187 AC XY: 136 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000716 AC: 32 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000908 AC: 101 AN: 1111846

Other (OTH) AF: 0.000364 AC: 22 AN: 60370

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74488

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.00176 AC: 27 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000223 Hom.: 1

Bravo AF: 0.000468

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.000291 AC: 35

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Enhanced S-cone syndrome (8)
6	-	-	not provided (6)
3	-	-	Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 (3)
3	-	-	Retinitis pigmentosa 37 (3)
2	-	-	Goldmann-Favre syndrome (2)
2	-	-	Retinal dystrophy (2)
1	-	-	Autosomal recessive retinitis pigmentosa (1)
1	-	-	Enhanced S-cone syndrome;CN239387:NR2E3-related disorder (1)
1	-	-	NR2E3-related disorder (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.059
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.0
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.11	T
Polyphen		0.63	P
Vest4		0.71
MVP		0.62
ClinPred		0.92	D
GERP RS		3.3
Varity_R		0.55
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.69		Position offset: 2

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

Other links and lift over

dbSNP: rs28937873; hg19: chr15-72105913;