rs1805022

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_014249.4(NR2E3):c.505C>T(p.Leu169Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,557,238 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 33 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 38 hom. )

Consequence

NR2E3
NM_014249.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.83

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Goldmann-Favre syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NR2E3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 15-71812110-C-T is Benign according to our data. Variant chr15-71812110-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260367.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP7

Synonymous conserved (PhyloP=2.83 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1900/152302) while in subpopulation AFR AF = 0.0431 (1793/41568). AF 95% confidence interval is 0.0415. There are 33 homozygotes in GnomAd4. There are 828 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4 link	c.505C>T	p.Leu169Leu	synonymous_variant	Exon 4 of 8	ENST00000617575.5	NP_055064.1	Q9Y5X4-1
NR2E3	NM_016346.4 link	c.505C>T	p.Leu169Leu	synonymous_variant	Exon 4 of 7		NP_057430.1	Q9Y5X4-2F1D8Q9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR2E3	ENST00000617575.5 link	c.505C>T	p.Leu169Leu	synonymous_variant	Exon 4 of 8	1	NM_014249.4	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1 link	c.505C>T	p.Leu169Leu	synonymous_variant	Exon 4 of 7	1		ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4 link	c.241C>T	p.Leu81Leu	synonymous_variant	Exon 6 of 10	2		ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1893

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00297

AC:

487

AN:

163782

AF XY:

0.00226

show subpopulations

Gnomad AFR exome

AF:

0.0481

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000761

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00134

AC:

1884

AN:

1404936

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

791

AN XY:

693652

show subpopulations

African (AFR)

AF:

0.0480

AC:

1530

AN:

31876

American (AMR)

AF:

0.00288

AC:

104

AN:

36166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.00

AC:

AN:

36190

South Asian (SAS)

AF:

0.0000752

AC:

AN:

79782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48898

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

1082790

Other (OTH)

AF:

0.00324

AC:

189

AN:

58296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

128

257

385

514

642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0125

AC:

1900

AN:

152302

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

828

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0431

AC:

1793

AN:

41568

American (AMR)

AF:

0.00484

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68020

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

188

282

376

470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00316

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Enhanced S-cone syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis Pigmentosa, Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Goldmann-Favre syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.1

(source)

DANN

Benign

0.54

PhyloP100

2.8

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

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rs1805022

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over