14-24082561-CA-AG

Variant names:

• chr14-24082561-CA-AG
• NM_001354768.3:c.287_288delTGinsCT
• NRL p.Met96Thr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_001354768.3(NRL):​c.287_288delTGinsCT​(p.Met96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: 32)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 0 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 1 ACMG points.

• 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.287_288delTGinsCT	p.Met96Thr	missense	N/A	NP_001341697.1	P54845-1
	NRL	NM_001354769.1		c.287_288delTGinsCT	p.Met96Thr	missense	N/A	NP_001341698.1	P54845-1
	NRL	NM_006177.5		c.287_288delTGinsCT	p.Met96Thr	missense	N/A	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.287_288delTGinsCT	p.Met96Thr	missense	N/A	ENSP00000454062.2	P54845-1
	NRL	ENST00000396997.1	TSL:1	c.287_288delTGinsCT	p.Met96Thr	missense	N/A	ENSP00000380193.1	P54845-1
	NRL	ENST00000397002.6	TSL:1	c.287_288delTGinsCT	p.Met96Thr	missense	N/A	ENSP00000380197.2	P54845-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-24551770;