rs104894459

Positions:

• chr14-24082701-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_001354768.3(NRL):​c.148T>A​(p.Ser50Thr) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S50L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• PP5: Variant 14-24082701-A-T is Pathogenic according to our data. Variant chr14-24082701-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 14042.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-24082701-A-T is described in UniProt as null. Variant chr14-24082701-A-T is described in UniProt as null. Variant chr14-24082701-A-T is described in UniProt as null. Variant chr14-24082701-A-T is described in Lovd as [Likely_pathogenic]. Variant chr14-24082701-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRL	NM_001354768.3	c.148T>A	p.Ser50Thr	missense_variant	2/3	ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRL	ENST00000561028.6	c.148T>A	p.Ser50Thr	missense_variant	2/3	2	NM_001354768.3	ENSP00000454062.2
NRL	ENST00000396997.1	c.148T>A	p.Ser50Thr	missense_variant	3/4	1		ENSP00000380193.1
NRL	ENST00000397002.6	c.148T>A	p.Ser50Thr	missense_variant	2/3	1		ENSP00000380197.2
NRL	ENST00000558280.1	c.148T>A	p.Ser50Thr	missense_variant	3/3	5		ENSP00000454180.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 27 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;N;N;D
REVEL	Pathogenic	0.84
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.061	T;T;T;D
Polyphen		1.0	D;D;D;.
Vest4		0.84
MutPred		0.69		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		0.23
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.81

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: rs104894459; hg19: chr14-24551910;