rs371620771
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_006393.3(NEBL):c.326T>C(p.Ile109Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,613,948 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I109V) has been classified as Uncertain significance.
Frequency
Consequence
NM_006393.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEBL | NM_006393.3 | c.326T>C | p.Ile109Thr | missense_variant | 4/28 | ENST00000377122.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEBL | ENST00000377122.9 | c.326T>C | p.Ile109Thr | missense_variant | 4/28 | 1 | NM_006393.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251410Hom.: 2 AF XY: 0.000103 AC XY: 14AN XY: 135874
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461670Hom.: 2 Cov.: 31 AF XY: 0.0000660 AC XY: 48AN XY: 727142
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152278Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 07, 2014 | p.Ile109Thr (ATT>ACT): c.326 T>C in exon 4 of the NEBL gene (NM_006393.2) Although rare, mutations in the NEBL gene have been reported in association with dilated cardiomyopathy (DCM) and endocardialfibroelastosis (Purevjav E at al., 2010). The I109T variant has not been published as a mutation or as a benign polymorphism to our knowledge. The I109T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In addition, the I109T 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. This substitution occurs at a position that is completely conserved across species. Nevertheless, in silico analysis is inconsistent in its prediction, but at least two models concur that this variant likely does not alter the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with a NEBL-related disorder, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 201900). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. This variant is present in population databases (rs371620771, gnomAD 0.05%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 109 of the NEBL protein (p.Ile109Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at