15-71810793-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_014249.4(NR2E3):​c.50C>T​(p.Ala17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 1,576,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A17A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

1
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.82
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.023731887).
BP6
Variant 15-71810793-C-T is Benign according to our data. Variant chr15-71810793-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 846003.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NR2E3NM_014249.4 linkuse as main transcriptc.50C>T p.Ala17Val missense_variant 1/8 ENST00000617575.5
NR2E3NM_016346.4 linkuse as main transcriptc.50C>T p.Ala17Val missense_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NR2E3ENST00000617575.5 linkuse as main transcriptc.50C>T p.Ala17Val missense_variant 1/81 NM_014249.4 P1Q9Y5X4-1
NR2E3ENST00000621098.1 linkuse as main transcriptc.50C>T p.Ala17Val missense_variant 1/71 Q9Y5X4-2
NR2E3ENST00000621736.4 linkuse as main transcriptc.-146-690C>T intron_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000432
AC:
8
AN:
185130
Hom.:
0
AF XY:
0.0000199
AC XY:
2
AN XY:
100254
show subpopulations
Gnomad AFR exome
AF:
0.000203
Gnomad AMR exome
AF:
0.0000354
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000813
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000383
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000330
AC:
47
AN:
1424188
Hom.:
0
Cov.:
31
AF XY:
0.0000199
AC XY:
14
AN XY:
705056
show subpopulations
Gnomad4 AFR exome
AF:
0.000154
Gnomad4 AMR exome
AF:
0.0000254
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000741
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000274
Gnomad4 OTH exome
AF:
0.0000509
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152316
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000474
Bravo
AF:
0.0000567
ExAC
AF:
0.0000424
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 09, 2022This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 17 of the NR2E3 protein (p.Ala17Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NR2E3-related conditions. ClinVar contains an entry for this variant (Variation ID: 846003). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Goldmann-Favre syndrome Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Aug 13, 2020- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.064
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
1.9
DANN
Benign
0.84
DEOGEN2
Benign
0.20
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.0067
N
LIST_S2
Benign
0.45
T;T
MetaRNN
Benign
0.024
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
N;N
PrimateAI
Uncertain
0.50
T
Sift4G
Benign
0.28
T;T
Polyphen
0.0010
B;.
Vest4
0.039
MVP
0.055
ClinPred
0.25
T
GERP RS
-1.0
Varity_R
0.025
gMVP
0.30

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.

Other links and lift over

dbSNP: rs534483995; hg19: chr15-72103133; COSMIC: COSV58907058; API