rs1555454566

chr15-71811552-CCTGCAACGG-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_014249.4(NR2E3):c.194_202del(p.Asn65_Cys67del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 1,445,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: NR2E3 NM_014249.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.66

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a zinc_finger_region NR C4-type (size 20) in uniprot entity NR2E3_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_014249.4
• PM4: Nonframeshift variant in NON repetitive region in NM_014249.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 15-71811552-CCTGCAACGG-C is Pathogenic according to our data. Variant chr15-71811552-CCTGCAACGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811552-CCTGCAACGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2E3	NM_014249.4	c.194_202del	p.Asn65_Cys67del	inframe_deletion	2/8	ENST00000617575.5
NR2E3	NM_016346.4	c.194_202del	p.Asn65_Cys67del	inframe_deletion	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2E3	ENST00000617575.5	c.194_202del	p.Asn65_Cys67del	inframe_deletion	2/8	1	NM_014249.4	P1
NR2E3	ENST00000621098.1	c.194_202del	p.Asn65_Cys67del	inframe_deletion	2/7	1
NR2E3	ENST00000621736.4	c.-71_-63del		5_prime_UTR_variant	4/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000135 AC: 3 AN: 222772 Hom.: 0 AF XY: 0.00000830 AC XY: 1 AN XY: 120544

Gnomad AFR exome AF: 0.0000776

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000899 AC: 13 AN: 1445784 Hom.: 0 AF XY: 0.00000976 AC XY: 7 AN XY: 717570

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000713

Gnomad4 ASJ exome AF: 0.000232

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Enhanced S-cone syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 21, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 17, 2020	- -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 29, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 551852). This variant has been observed in individual(s) with autosomal recessive enhanced S-cone syndrome/Goldmann-Favre syndrome (PMID: 12963616, 19273793, 19898638, 21364904, 28541266). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant, c.194_202del, results in the deletion of 3 amino acid(s) of the NR2E3 protein (p.Asn65_Cys67del), but otherwise preserves the integrity of the reading frame. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 13, 2019

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555454566; hg19: chr15-72103892;