rs104894459

Variant names:

• chr14-24082701-A-G
• rs104894459
• NM_001354768.3:c.148T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-24082701-A-G
• chr14-24082701-A-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001354768.3(NRL):​c.148T>C​(p.Ser50Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S50T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.28
• 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001354768.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24082701-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14042.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 14-24082701-A-G is Pathogenic according to our data. Variant chr14-24082701-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2137571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRL	NM_001354768.3	c.148T>C	p.Ser50Pro	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.148T>C	p.Ser50Pro	missense_variant	Exon 2 of 3	2	NM_001354768.3	ENSP00000454062.2
NRL	ENST00000396997.1	c.148T>C	p.Ser50Pro	missense_variant	Exon 3 of 4	1		ENSP00000380193.1
NRL	ENST00000397002.6	c.148T>C	p.Ser50Pro	missense_variant	Exon 2 of 3	1		ENSP00000380197.2
NRL	ENST00000558280.1	c.148T>C	p.Ser50Pro	missense_variant	Exon 3 of 3	5		ENSP00000454180.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Aug 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser50 amino acid residue in NRL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11879142, 17335001, 33691693). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects NRL function (PMID: 17335001). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 11879142; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 50 of the NRL protein (p.Ser50Pro). -

Retinal dystrophy Pathogenic:1

Jan 01, 2014

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;.
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Benign	0.17	T;T;T;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.81
MutPred		0.67		Gain of catalytic residue at P48 (P = 0);Gain of catalytic residue at P48 (P = 0);Gain of catalytic residue at P48 (P = 0);Gain of catalytic residue at P48 (P = 0);
MVP		0.98
MPC		0.26
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.82
Mutation Taster		=10/90	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: rs104894459; hg19: chr14-24551910;