rs377257254

Variant names:

• chr15-71813408-C-A
• rs377257254
• NM_014249.4:c.767C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-71813408-C-A
• chr15-71813408-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM5 PP3_Moderate PP5_Very_Strong

The NM_014249.4(NR2E3):​c.767C>A​(p.Ala256Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,611,394 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. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000950160: Experimental studies have shown that this missense change affects NR2E3 function (PMID:19898638, 25703721, 28300834)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A256V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.83
• Publications: 16 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000950160: Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638, 25703721, 28300834).; SCV001824694: Published functional studies demonstrate impairment of protein localization, binding, and function (PMID: 19898638, 28300834); SCV001653112: "In vitro functional studies support an impact on protein function (Kanda 2009 PMID: 19898638, von Alpen 2015 PMID: 25703721)."; SCV006323236: Relevant functional assessments of this variant are available in the literature (PMID: 19898638, 25703721).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-71813408-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 844032.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 15-71813408-C-A is Pathogenic according to our data. Variant chr15-71813408-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438229.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.767C>A	p.Ala256Glu	missense	Exon 6 of 8	NP_055064.1	Q9Y5X4-1
	NR2E3	NM_016346.4		c.767C>A	p.Ala256Glu	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.767C>A	p.Ala256Glu	missense	Exon 6 of 8	ENSP00000482504.1	Q9Y5X4-1
	NR2E3	ENST00000621098.1	TSL:1	c.767C>A	p.Ala256Glu	missense	Exon 6 of 7	ENSP00000479962.1	Q9Y5X4-2
	NR2E3	ENST00000621736.4	TSL:2	c.503C>A	p.Ala168Glu	missense	Exon 8 of 10	ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000371 AC: 9 AN: 242284 AF XY: 0.0000380

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.0000882

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000460

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 249 AN: 1459192 Hom.: 0 Cov.: 32 AF XY: 0.000156 AC XY: 113 AN XY: 725564

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.0000675 AC: 3 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000216 AC: 240 AN: 1110942

Other (OTH) AF: 0.0000663 AC: 4 AN: 60302

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Enhanced S-cone syndrome (2)
2	-	-	not provided (2)
2	-	-	Retinal dystrophy (2)
1	-	-	Goldmann-Favre syndrome (1)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Retinitis pigmentosa 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	30
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.91
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.80

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

Other links and lift over

dbSNP: rs377257254; hg19: chr15-72105748;