14-24081123-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001354768.3(NRL):c.*113C>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 0.00753 in 657,102 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (26 hom.)
• Consequence: NRL NM_001354768.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0160

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=-0.69).
• BP6: Variant 14-24081123-G-T is Benign according to our data. Variant chr14-24081123-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 312938.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00551 (840/152364) while in subpopulation NFE AF= 0.00988 (672/68032). AF 95% confidence interval is 0.00926. There are 5 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRL	NM_001354768.3	c.*113C>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.*113C>A		3_prime_UTR_variant	3/3	2	NM_001354768.3	P1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 839 AN: 152246 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00988

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00814 AC: 4109 AN: 504738 Hom.: 26 Cov.: 8 AF XY: 0.00808 AC XY: 2023 AN XY: 250338

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00220

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.00338

Gnomad4 NFE exome AF: 0.00982

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.00551 AC: 840 AN: 152364 Hom.: 5 Cov.: 33 AF XY: 0.00501 AC XY: 373 AN XY: 74504

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.00988

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00405 Hom.: 1

Bravo AF: 0.00504

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	7.0
Dann	Benign	0.84

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: rs3560; hg19: chr14-24550332;