rs397514516

Variant names:

• chr14-24082562-A-G
• rs397514516
• NM_001354768.3:c.287T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001354768.3(NRL):​c.287T>C​(p.Met96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.07

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRL	NM_001354768.3	c.287T>C	p.Met96Thr	missense_variant	Exon 2 of 3	ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRL	ENST00000561028.6	c.287T>C	p.Met96Thr	missense_variant	Exon 2 of 3	2	NM_001354768.3	ENSP00000454062.2
NRL	ENST00000396997.1	c.287T>C	p.Met96Thr	missense_variant	Exon 3 of 4	1		ENSP00000380193.1
NRL	ENST00000397002.6	c.287T>C	p.Met96Thr	missense_variant	Exon 2 of 3	1		ENSP00000380197.2
NRL	ENST00000558280.1	c.*92T>C		downstream_gene_variant		5		ENSP00000454180.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249840 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 27 Pathogenic:1

Nov 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 96 of the NRL protein (p.Met96Thr). This variant is present in population databases (rs397514516, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 21981118). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39510). 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 tolerated. Experimental studies have shown that this missense change affects NRL function (PMID: 21981118). 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. -

Retinal dystrophy Uncertain:1

May 14, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T;T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.39	N
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.88	N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.067	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.70
MutPred		0.55		Gain of glycosylation at M96 (P = 0.0254);Gain of glycosylation at M96 (P = 0.0254);Gain of glycosylation at M96 (P = 0.0254);
MVP		0.78
MPC		0.034
ClinPred		0.089	T
GERP RS		1.5
Varity_R		0.42
gMVP		0.70

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: rs397514516; hg19: chr14-24551771;