rs1805023

Positions:

• chr15-71812458-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014249.4(NR2E3):​c.694G>A​(p.Val232Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,613,730 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (10 hom.)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.74

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain NR LBD (size 241) in uniprot entity NR2E3_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_014249.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008600444).
• BP6: Variant 15-71812458-G-A is Benign according to our data. Variant chr15-71812458-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71812458-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0063 (959/152228) while in subpopulation AFR AF= 0.022 (912/41528). AF 95% confidence interval is 0.0208. There are 9 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2E3	NM_014249.4	c.694G>A	p.Val232Ile	missense_variant	5/8	ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.694G>A	p.Val232Ile	missense_variant	5/7		NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5	c.694G>A	p.Val232Ile	missense_variant	5/8	1	NM_014249.4	ENSP00000482504	P1
NR2E3	ENST00000621098.1	c.694G>A	p.Val232Ile	missense_variant	5/7	1		ENSP00000479962
NR2E3	ENST00000621736.4	c.430G>A	p.Val144Ile	missense_variant	7/10	2		ENSP00000479254

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 956 AN: 152110 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000588

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00170 AC: 423 AN: 248720 Hom.: 5 AF XY: 0.00116 AC XY: 156 AN XY: 134918

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000657 AC: 960 AN: 1461502 Hom.: 10 Cov.: 33 AF XY: 0.000521 AC XY: 379 AN XY: 727032

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00630 AC: 959 AN: 152228 Hom.: 9 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74444

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00120 Hom.: 3

Bravo AF: 0.00728

ESP6500AA AF: 0.0191 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00212 AC: 256

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Enhanced S-cone syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 13, 2017

- -

Goldmann-Favre syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Retinitis pigmentosa 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Benign	0.75
DEOGEN2	Uncertain	0.54	.;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.22	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.19
MVP		0.39
ClinPred		0.17	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.43

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

Other links and lift over

dbSNP: rs1805023; hg19: chr15-72104798;