14-24080678-G-A

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.*558C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 152,698 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (0 hom.)
• Consequence: NRL NM_001354768.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-24080678-G-A is Benign according to our data. Variant chr14-24080678-G-A is described in ClinVar as [Benign]. Clinvar id is 312931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRL	NM_001354768.3	c.*558C>T		3_prime_UTR_variant	3/3	ENST00000561028.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRL	ENST00000561028.6	c.*558C>T		3_prime_UTR_variant	3/3	2	NM_001354768.3	P1
NRL	ENST00000397002.6	c.*558C>T		3_prime_UTR_variant	3/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1067 AN: 152100 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00208 AC: 1 AN: 480 Hom.: 0 Cov.: 0 AF XY: 0.00331 AC XY: 1 AN XY: 302

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00703 AC: 1070 AN: 152218 Hom.: 6 Cov.: 32 AF XY: 0.00697 AC XY: 519 AN XY: 74430

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00831

Asia WGS AF: 0.00202 AC: 7 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	-0.75
Cadd	Benign	0.73
Dann	Benign	0.75

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: rs114327952; hg19: chr14-24549887;