rs146471913
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006393.3(NEBL):c.1837C>T(p.Arg613Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,612,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R613R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006393.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEBL | NM_006393.3 | c.1837C>T | p.Arg613Ter | stop_gained | 18/28 | ENST00000377122.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEBL | ENST00000377122.9 | c.1837C>T | p.Arg613Ter | stop_gained | 18/28 | 1 | NM_006393.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152100Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000152 AC: 38AN: 250746Hom.: 0 AF XY: 0.000207 AC XY: 28AN XY: 135514
GnomAD4 exome AF: 0.000292 AC: 427AN: 1460544Hom.: 0 Cov.: 30 AF XY: 0.000271 AC XY: 197AN XY: 726670
GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152100Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74286
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2014 | The Arg613X variant in NEBL has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs146471913). This nonsense variant leads to a premature termination codon at p osition 613, which is predicted to lead to a truncated or absent protein. Missen se variants in NEBL have been reported in individuals with DCM and endocardial f ibroelastosis, and mouse studies provide support for a role of this gene in the etiology of dilated cardiomyopathy (Purevjav 2010), but the spectrum of variants for this gene has not been fully elucidated. In summary, additional studies are needed to fully assess the clinical significance of this variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not an established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg613*) in the NEBL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NEBL cause disease. This variant is present in population databases (rs146471913, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 178096). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function is an unlikely mechanism of disease, as null mouse models have normal cardiac function (PMID: 25987543). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (44 heterozygotes, 0 homozygotes). (SP) 0710 - Other NMD predicted variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at