rs114875104
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_006393.3(NEBL):c.2080C>T(p.Arg694Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R694Q) has been classified as Likely benign.
Frequency
Consequence
NM_006393.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEBL | NM_006393.3 | c.2080C>T | p.Arg694Trp | missense_variant | 21/28 | ENST00000377122.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEBL | ENST00000377122.9 | c.2080C>T | p.Arg694Trp | missense_variant | 21/28 | 1 | NM_006393.3 |
Frequencies
GnomAD3 genomes ? AF: 0.000559 AC: 85AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000167 AC: 42AN: 251062Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135680
GnomAD4 exome AF: 0.000142 AC: 207AN: 1461216Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84AN XY: 726984
GnomAD4 genome ? AF: 0.000558 AC: 85AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38AN XY: 74420
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2021 | The c.2080C>T (p.R694W) alteration is located in exon 21 (coding exon 21) of the NEBL gene. This alteration results from a C to T substitution at nucleotide position 2080, causing the arginine (R) at amino acid position 694 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 23, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Arg694Trp varia nt in NEBL has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.16% (7/4406) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs114875104). This frequency is too l ow to rule out a role in disease. Arginine (Arg) at position 694 is not conserve d in evolution, suggesting that a change to this position may be tolerated. This variant is less likely disease causing but additional studies are needed to ful ly assess its clinical significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2017 | A variant of uncertain significance has been identified in the NEBL gene. The R694W variant has not been published as a pathogenic variant or reported as a benign variant, to our knowledge. The NHLBI Exome Sequencing Project, Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project reports R694W was observed in 0.1-0.2% of individuals of African background, indicating it may be a rare (benign) variant in this population. This substitution occurs at a position that is not conserved across species. Nevertheless, the R694W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | NEBL NM_006393.2 exon 25 p.Arg694Trp (c.2080C>T): This variant has not been reported in the literature and is present in 0.1% (38/24960) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-21106597-G-A). This variant is present in ClinVar (Variation ID:45491). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
NEBL-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 24, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Primary dilated cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at