rs146403122

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014249.4(NR2E3):c.361G>A(p.Glu121Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,550,932 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 51 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.64

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008704543).

BP6

Variant 15-71811966-G-A is Benign according to our data. Variant chr15-71811966-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811966-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00231 (352/152318) while in subpopulation EAS AF= 0.0444 (230/5176). AF 95% confidence interval is 0.0397. There are 4 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2E3	NM_014249.4 linkuse as main transcript	c.361G>A	p.Glu121Lys	missense_variant	4/8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4 linkuse as main transcript	c.361G>A	p.Glu121Lys	missense_variant	4/7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5 linkuse as main transcript	c.361G>A	p.Glu121Lys	missense_variant	4/8	1	NM_014249.4	ENSP00000482504	P1	Q9Y5X4-1
NR2E3	ENST00000621098.1 linkuse as main transcript	c.361G>A	p.Glu121Lys	missense_variant	4/7	1		ENSP00000479962		Q9Y5X4-2
NR2E3	ENST00000621736.4 linkuse as main transcript	c.97G>A	p.Glu33Lys	missense_variant	6/10	2		ENSP00000479254

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

352

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0443

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00432

AC:

665

AN:

153770

Hom.:

AF XY:

0.00425

AC XY:

348

AN XY:

81862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.000353

Gnomad EAS exome

AF:

0.0495

Gnomad SAS exome

AF:

0.000484

Gnomad FIN exome

AF:

0.00503

Gnomad NFE exome

AF:

0.000433

Gnomad OTH exome

AF:

0.00276

GnomAD4 exome

AF:

0.00172

AC:

2401

AN:

1398614

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1119

AN XY:

689944

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000559

Gnomad4 ASJ exome

AF:

0.000556

Gnomad4 EAS exome

AF:

0.0407

Gnomad4 SAS exome

AF:

0.000757

Gnomad4 FIN exome

AF:

0.00659

Gnomad4 NFE exome

AF:

0.000406

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.00231

AC:

352

AN:

152318

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

201

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0444

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00480

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.00218

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000124

AC:

ExAC

AF:

0.00207

AC:

212

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NR2E3: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 31, 2017	- -

Enhanced S-cone syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 17, 2020

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Benign

0.80

DEOGEN2

Uncertain

0.60

.;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.5

.;M;M

PrimateAI

Uncertain

0.78

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.92

MVP

0.69

ClinPred

0.24

GERP RS

4.5

Varity_R

0.29

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over