rs104894463

Variant names:

• chr14-24081471-A-G
• rs104894463
• NM_001354768.3:c.479T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP2 PP3_Strong PP5_Moderate

The NM_006177.5(NRL):​c.479T>C​(p.Leu160Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,434,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NRL NM_006177.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22
• Publications: 11 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: Likely_pathogenic. The variant received 7 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 retinitis pigmentosa 27, retinitis pigmentosa, enhanced S-cone syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 14-24081471-A-G is Pathogenic according to our data. Variant chr14-24081471-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 14044.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006177.5. 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.479T>C	p.Leu160Pro	missense	Exon 3 of 3	NP_001341697.1
	NRL	NM_001354769.1		c.479T>C	p.Leu160Pro	missense	Exon 4 of 4	NP_001341698.1
	NRL	NM_006177.5		c.479T>C	p.Leu160Pro	missense	Exon 4 of 4	NP_006168.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRL	ENST00000561028.6	TSL:2 MANE Select	c.479T>C	p.Leu160Pro	missense	Exon 3 of 3	ENSP00000454062.2
	NRL	ENST00000396997.1	TSL:1	c.479T>C	p.Leu160Pro	missense	Exon 4 of 4	ENSP00000380193.1
	NRL	ENST00000397002.6	TSL:1	c.479T>C	p.Leu160Pro	missense	Exon 3 of 3	ENSP00000380197.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1434236 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 10 AN XY: 711450

African (AFR) AF: 0.00 AC: 0 AN: 33050

American (AMR) AF: 0.00 AC: 0 AN: 40902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 38532

South Asian (SAS) AF: 0.00 AC: 0 AN: 82582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1101518

Other (OTH) AF: 0.00 AC: 0 AN: 59414

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	ENHANCED S-CONE SYNDROME 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.77		Gain of glycosylation at L160 (P = 0.0185)
MVP		1.0
MPC		3.6
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.072	Neutral
Varity_R		0.99
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs104894463; hg19: chr14-24550680;