chr14-24081471-A-G

Position:

• chr14-24081471-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_001354768.3(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_001354768.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22

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.

• 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 id is 14044.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-24081471-A-G is described in UniProt as null. Variant chr14-24081471-A-G is described in UniProt as null. Variant chr14-24081471-A-G is described in UniProt as null. Variant chr14-24081471-A-G is described in Lovd as [Likely_pathogenic]. Variant chr14-24081471-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRL	NM_001354768.3	c.479T>C	p.Leu160Pro	missense_variant	3/3	ENST00000561028.6	NP_001341697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRL	ENST00000561028.6	c.479T>C	p.Leu160Pro	missense_variant	3/3	2	NM_001354768.3	ENSP00000454062.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

ClinVar contains an entry for this variant (Variation ID: 14044). This missense change has been observed in individual(s) with retinal dystrophy (PMID: 15591106, 28341476). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 160 of the NRL protein (p.Leu160Pro). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects NRL function (PMID: 15591106, 17335001). -

Retinal degeneration, autosomal recessive, clumped pigment type 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	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;D;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;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;M;.;.
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.98
MutPred		0.77		Gain of glycosylation at L160 (P = 0.0185);Gain of glycosylation at L160 (P = 0.0185);Gain of glycosylation at L160 (P = 0.0185);.;.;
MVP		1.0
MPC		3.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.91

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: rs104894463; hg19: chr14-24550680;