rs1555339028

Variant names:

• chr14-24081483-T-TCGTCGCGCCCGCAGCCCCG
• rs1555339028
• NM_001354768.3:c.448_466dupCGGGGCTGCGGGCGCGACG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001354768.3(NRL):​c.448_466dupCGGGGCTGCGGGCGCGACG​(p.Glu156AlafsTer71) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000139 in 1,441,636 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NRL NM_001354768.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.98
• Publications: 0 publications found

Genes affected

NRL (HGNC:8002): (neural retina leucine zipper) This gene encodes a basic motif-leucine zipper transcription factor of the Maf subfamily. The encoded protein is conserved among vertebrates and is a critical intrinsic regulator of photoceptor development and function. Mutations in this gene have been associated with retinitis pigmentosa and retinal degenerative diseases. [provided by RefSeq, Jul 2008]

NRL Gene-Disease associations (from GenCC):

• retinitis pigmentosa 27

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• enhanced S-cone syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRL	NM_001354768.3	c.448_466dupCGGGGCTGCGGGCGCGACG	p.Glu156AlafsTer71	frameshift_variant	Exon 3 of 3	ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRL	ENST00000561028.6	c.448_466dupCGGGGCTGCGGGCGCGACG	p.Glu156AlafsTer71	frameshift_variant	Exon 3 of 3	2	NM_001354768.3	ENSP00000454062.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441636 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715818

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 42062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 38868

South Asian (SAS) AF: 0.00 AC: 0 AN: 83380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104960

Other (OTH) AF: 0.00 AC: 0 AN: 59662

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Albinism;C0235996:Elevated circulating hepatic transaminase concentration;C0600518:Choroidal neovascularization;C1853141:Slow decrease in visual acuity;C2673946:Foveal hypoplasia;C4021768:Abnormality of metabolism/homeostasis Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu156Alafs*71) in the NRL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the NRL protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NRL-related conditions. ClinVar contains an entry for this variant (Variation ID: 523490). This variant disrupts a region of the NRL protein in which other variant(s) (p.Cys219Valfs*4) have been observed in individuals with NRL-related conditions (PMID: 29385733). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0

Splicing

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

Other links and lift over

dbSNP: rs1555339028; hg19: chr14-24550692;