chr14-24082562-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.07
• Publications: 6 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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 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 enhanced S-cone syndrome, retinitis pigmentosa 27, retinitis pigmentosa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354768.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRL	NM_001354768.3	MANE Select	c.287T>C	p.Met96Thr	missense	Exon 2 of 3	NP_001341697.1	P54845-1
	NRL	NM_001354769.1		c.287T>C	p.Met96Thr	missense	Exon 3 of 4	NP_001341698.1	P54845-1
	NRL	NM_006177.5		c.287T>C	p.Met96Thr	missense	Exon 3 of 4	NP_006168.1	P54845-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRL	ENST00000561028.6	TSL:2 MANE Select	c.287T>C	p.Met96Thr	missense	Exon 2 of 3	ENSP00000454062.2	P54845-1
	NRL	ENST00000396997.1	TSL:1	c.287T>C	p.Met96Thr	missense	Exon 3 of 4	ENSP00000380193.1	P54845-1
	NRL	ENST00000397002.6	TSL:1	c.287T>C	p.Met96Thr	missense	Exon 2 of 3	ENSP00000380197.2	P54845-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249840 AF XY: 0.00000738

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa 27 (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.067	T
Polyphen		0.0010	B
Vest4		0.70
MutPred		0.55		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
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs397514516; hg19: chr14-24551771;