rs104894463

Positions:

• chr14-24081471-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_001354768.3(NRL):​c.479T>C​(p.Leu160Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,434,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22

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 Likely_pathogenic. Variant got 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 14-24081471-A-G is Pathogenic according to our data. Variant chr14-24081471-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14044.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-24081471-A-G is described in UniProt as null. Variant chr14-24081471-A-G is described in UniProt as null. Variant chr14-24081471-A-G is described in UniProt as null. Variant chr14-24081471-A-G is described in Lovd as [Likely_pathogenic]. Variant chr14-24081471-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRL	NM_001354768.3	c.479T>C	p.Leu160Pro	missense_variant	3/3	ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRL	ENST00000561028.6	c.479T>C	p.Leu160Pro	missense_variant	3/3	2	NM_001354768.3	ENSP00000454062	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1434236 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 10 AN XY: 711450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 160 of the NRL protein (p.Leu160Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinal dystrophy (PMID: 15591106, 28341476). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14044). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NRL function (PMID: 15591106, 17335001). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Retinal degeneration, autosomal recessive, clumped pigment type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.98
MutPred		0.77		Gain of glycosylation at L160 (P = 0.0185);Gain of glycosylation at L160 (P = 0.0185);Gain of glycosylation at L160 (P = 0.0185);.;.;
MVP		1.0
MPC		3.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.91

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

Other links and lift over

dbSNP: rs104894463; hg19: chr14-24550680;