rs794727281

chr14-24082698-G-Achr14-24082698-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001354768.3(NRL):c.151C>T(p.Pro51Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P51L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24082697-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 916413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 14-24082698-G-A is Pathogenic according to our data. Variant chr14-24082698-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24082698-G-A is described in UniProt as null. Variant chr14-24082698-G-A is described in UniProt as null. Variant chr14-24082698-G-A is described in UniProt as null. Variant chr14-24082698-G-A is described in Lovd as [Pathogenic]. Variant chr14-24082698-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRL	NM_001354768.3	c.151C>T	p.Pro51Ser	missense_variant	2/3	ENST00000561028.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRL	ENST00000561028.6	c.151C>T	p.Pro51Ser	missense_variant	2/3	2	NM_001354768.3	P1
NRL	ENST00000396997.1	c.151C>T	p.Pro51Ser	missense_variant	3/4	1		P1
NRL	ENST00000397002.6	c.151C>T	p.Pro51Ser	missense_variant	2/3	1		P1
NRL	ENST00000558280.1	c.151C>T	p.Pro51Ser	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 51 of the NRL protein (p.Pro51Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 15591106; Invitae). ClinVar contains an entry for this variant (Variation ID: 195258). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25"). Experimental studies have shown that this missense change affects NRL function (PMID: 15591106). This variant disrupts the p.Pro51 amino acid residue in NRL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11385710, 11879142, 17335001, 21981118). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	Published functional studies demonstrate a damaging effect with a decrease in NRL isoforms upon phosphatase treatment and an increase in transactivation of the rhodopsin promoter, consistent with decreased NRL phosphorylation (Kanda et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11879142, 10627948, 28106895, 21981118, 19933183, 19501669, 15591106, 32962414, 17335001, 11385710) -

Retinitis pigmentosa 27 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The NRL c.151C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM1, PS3. Based on this evidence we have classified this variant as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.24	T;T;T;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.78
MutPred		0.74		Gain of catalytic residue at P48 (P = 0);Gain of catalytic residue at P48 (P = 0);Gain of catalytic residue at P48 (P = 0);Gain of catalytic residue at P48 (P = 0);
MVP		0.98
MPC		0.24
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs794727281; hg19: chr14-24551907;