chr14-24082625-A-AG
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001354768.3(NRL):βc.223_224insCβ(p.Leu75ProfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L75L) has been classified as Likely benign.
Frequency
Consequence
NM_001354768.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRL | NM_001354768.3 | c.223_224insC | p.Leu75ProfsTer19 | frameshift_variant | 2/3 | ENST00000561028.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRL | ENST00000561028.6 | c.223_224insC | p.Leu75ProfsTer19 | frameshift_variant | 2/3 | 2 | NM_001354768.3 | P1 | |
NRL | ENST00000396997.1 | c.223_224insC | p.Leu75ProfsTer19 | frameshift_variant | 3/4 | 1 | P1 | ||
NRL | ENST00000397002.6 | c.223_224insC | p.Leu75ProfsTer19 | frameshift_variant | 2/3 | 1 | P1 | ||
NRL | ENST00000558280.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249564Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135362
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461646Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727126
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 10, 2023 | This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive NRL-related disorders (PMID: 15591106, 25412400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14043). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs763191889, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Leu75Profs*19) in the NRL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NRL are known to be pathogenic (PMID: 11694879, 15591106). - |
Retinal degeneration, autosomal recessive, clumped pigment type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
Retinitis pigmentosa 27 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 12, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at