chr14-24082758-G-C

Variant names:

• chr14-24082758-G-C
• rs762991211
• NM_001354768.3:c.91C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001354768.3(NRL):​c.91C>G​(p.Arg31Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRL NM_001354768.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 enhanced S-cone syndrome, retinitis pigmentosa 27, retinitis pigmentosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31345522).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354768.3. 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.91C>G	p.Arg31Gly	missense	Exon 2 of 3	NP_001341697.1	P54845-1
	NRL	NM_001354769.1		c.91C>G	p.Arg31Gly	missense	Exon 3 of 4	NP_001341698.1	P54845-1
	NRL	NM_006177.5		c.91C>G	p.Arg31Gly	missense	Exon 3 of 4	NP_006168.1	P54845-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRL	ENST00000561028.6	TSL:2 MANE Select	c.91C>G	p.Arg31Gly	missense	Exon 2 of 3	ENSP00000454062.2	P54845-1
	NRL	ENST00000396997.1	TSL:1	c.91C>G	p.Arg31Gly	missense	Exon 3 of 4	ENSP00000380193.1	P54845-1
	NRL	ENST00000397002.6	TSL:1	c.91C>G	p.Arg31Gly	missense	Exon 2 of 3	ENSP00000380197.2	P54845-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.015	D
Sift4G	Benign	0.11	T
Polyphen		0.36	B
Vest4		0.33
MutPred		0.29		Gain of catalytic residue at P34 (P = 8e-04)
MVP		0.92
MPC		0.041
ClinPred		0.28	T
GERP RS		3.4
Varity_R		0.18
gMVP		0.58
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs762991211; hg19: chr14-24551967;