15-71811481-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014249.4(NR2E3):c.119-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000257 in 1,554,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NR2E3
NM_014249.4 splice_acceptor, intron

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.05

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 was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-71811481-A-G is Pathogenic according to our data. Variant chr15-71811481-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1361677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811481-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4 link	c.119-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 7	ENST00000617575.5	NP_055064.1	Q9Y5X4-1
NR2E3	NM_016346.4 link	c.119-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 6		NP_057430.1	Q9Y5X4-2F1D8Q9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR2E3	ENST00000617575.5 link	c.119-2A>G	splice_acceptor_variant, intron_variant	Intron 1 of 7	1	NM_014249.4	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1 link	c.119-2A>G	splice_acceptor_variant, intron_variant	Intron 1 of 6	1		ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4 link	c.-146-2A>G	splice_acceptor_variant, intron_variant	Intron 3 of 9	2		ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1402938

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692406

show subpopulations

Gnomad4 AFR exome

AF:

0.0000630

AC:

AN:

31742

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35974

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25226

Gnomad4 EAS exome

AF:

0.0000278

AC:

AN:

35970

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

79476

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

49494

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1081972

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

58164

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.0000242

AC:

0.0000241569

AN:

0.0000241569

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18294254). ClinVar contains an entry for this variant (Variation ID: 1361677). Disruption of this splice site has been observed in individual(s) with autosomal recessive enhanced S-cone syndrome (PMID: 10655056, 24474277, 25079116). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the NR2E3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NR2E3 are known to be pathogenic (PMID: 15459973, 27522502). -

Enhanced S-cone syndrome

Pathogenic:1

Oct 25, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Benign

0.92

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.65

GERP RS

3.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.95

Position offset: 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