14-24081015-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001354768.3(NRL):c.*221G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 390,378 control chromosomes in the GnomAD database, including 69,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (22706 hom., cov: 32)
  • Exomes 𝑓: 0.62 (47271 hom.)
• Consequence: NRL NM_001354768.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.298

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 14-24081015-C-T is Benign according to our data. Variant chr14-24081015-C-T is described in ClinVar as [Benign]. Clinvar id is 312935.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRL	NM_001354768.3	c.*221G>A		3_prime_UTR_variant	3/3	ENST00000561028.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRL	ENST00000561028.6	c.*221G>A		3_prime_UTR_variant	3/3	2	NM_001354768.3	P1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76664 AN: 151866 Hom.: 22701 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.512

GnomAD4 exome AF: 0.621 AC: 147927 AN: 238394 Hom.: 47271 Cov.: 3 AF XY: 0.622 AC XY: 75218 AN XY: 120998

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.656

Gnomad4 EAS exome AF: 0.465

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.586

GnomAD4 genome AF: 0.504 AC: 76670 AN: 151984 Hom.: 22706 Cov.: 32 AF XY: 0.504 AC XY: 37404 AN XY: 74272

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.659

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.514

Alfa AF: 0.634 Hom.: 47150

Bravo AF: 0.482

Asia WGS AF: 0.481 AC: 1678 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Benign	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: rs3561; hg19: chr14-24550224;