chr14-24082562-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M96I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NRL
NM_001354768.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 2.07

Publications

6 publications found

Variant links:

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

NRL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.61398 (below the threshold of 3.09). Trascript score misZ: -0.58033 (below the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa 27, retinitis pigmentosa, enhanced S-cone syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRL	NM_001354768.3 link	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	UniProt
NRL	ENST00000561028.6 link	c.287T>C	p.Met96Thr	missense_variant	Exon 2 of 3	2	NM_001354768.3	ENSP00000454062.2	P54845-1
NRL	ENST00000396997.1 link	c.287T>C	p.Met96Thr	missense_variant	Exon 3 of 4	1		ENSP00000380193.1	P54845-1
NRL	ENST00000397002.6 link	c.287T>C	p.Met96Thr	missense_variant	Exon 2 of 3	1		ENSP00000380197.2	P54845-1
NRL	ENST00000558280.1 link	c.*92T>C		downstream_gene_variant		5		ENSP00000454180.1	H0YNW2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249840

AF XY:

0.00000738

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461348

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52888

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000896

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

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

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.81

L;L;L

PhyloP100

2.1

PrimateAI

Benign

0.40

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

GERP RS

1.5

Varity_R

0.42

gMVP

0.70

Mutation Taster

=7/93

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over