chr1-77942158-T-TA
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2
The NM_144573.4(NEXN):βc.1609_1610insAβ(p.Leu537TyrfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. L537L) has been classified as Likely benign.
Frequency
Consequence
NM_144573.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248826Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134996
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461538Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727066
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Leu537Tyrfs*7) in the NEXN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acid(s) of the NEXN protein. This variant is present in population databases (rs779350415, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 283614). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 12, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2016 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu537fs variant in NEXN has not been previously reported in individuals with cardiomyopa thy, but has been identified in 1/66208 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs779350415). This variant is predicted to cause a frameshift, which alters the protein?s amino ac id sequence beginning at position 537 and leads to a premature termination codon 7 amino acids downstream. Although the severe nature of this change increases t he likelihood that the variant is pathogenic, the NEXN gene has not been widely studied and the spectrum of variants leading to disease is not well-defined. Los s of NEXN function has been shown to cause DCM in zebrafish; however, it remains unclear if one or both copies of the gene need to be affected to cause disease (Hassel 2009, Wang 2010). In summary, while there is some suspicion for a pathog enic role, the clinical significance of the p.Leu537fs variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 12, 2015 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Apr 23, 2019 | This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at