chr1-77929505-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2
The NM_144573.4(NEXN):c.1053+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000747 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_144573.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.1053+1G>A | splice_donor_variant, intron_variant | ENST00000334785.12 | NP_653174.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.1053+1G>A | splice_donor_variant, intron_variant | 1 | NM_144573.4 | ENSP00000333938.7 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000324 AC: 8AN: 246862Hom.: 0 AF XY: 0.0000373 AC XY: 5AN XY: 134144
GnomAD4 exome AF: 0.0000747 AC: 109AN: 1459720Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 726198
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NEXN c.1053+1G>A variant was identified in 1 of 312 proband chromosomes (frequency: 0.0032) from individuals with dilated cardiomyopathy (Walsh_2017_PMID:27532257; Pugh_2014_PMID:24503780). The variant was identified in dbSNP (ID: rs397517843) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Blueprint Genetics, Laboratory for Molecular Medicine and Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute). The variant was identified in control databases in 8 of 246862 chromosomes at a frequency of 0.00003241 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 8 of 110632 chromosomes (freq: 0.000072), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.1053+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the loss of the canonical 5' splice site. However, this has not been confirmed by RNA analysis. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2019 | Identified in patients with DCM in the published literature (Pugh et al., 2014; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 47886; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 24503780, 27532257, 31514951) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 14, 2023 | This sequence change affects a donor splice site in intron 9 of the NEXN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEXN are known to be pathogenic (PMID: 32058062, 32814711, 32870709, 33949776). This variant is present in population databases (rs397517843, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 31514951). ClinVar contains an entry for this variant (Variation ID: 47886). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Apr 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 27, 2018 | The c.1053+1G>A variant in NEXN has been identified by our laboratory in 1 infan t with cardiomyopathy and a family history of DCM. This variant did not segregat e with disease in this family, and affected individuals carried another likely p athogenic variant in ATCT1. This variant has been identified in 9/109006 Europea n chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs397517843). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicin g leading to an abnormal or absent protein. NEXN variants have been described i n individuals with DCM and HCM but they are rare and overall poorly studied. In summary, the clinical significance of the c.1053+1G>A variant is uncertain. ACMG /AMP Criteria applied: PP3. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 05, 2019 | - - |
Hypertrophic cardiomyopathy 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 06, 2022 | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 22, 2015 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2020 | The c.1053+1G>A intronic alteration consists of a G to A substitution nucleotides after coding exon 8 in the NEXN gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
NEXN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 28, 2023 | The NEXN c.1053+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in individuals with dilated cardiomyopathy phenotypes (Supplemental Table 1, Pugh et al 2014. PubMed ID: 24503780; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant is reported in 0.0072% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-78395190-G-A). Loss of function variants in NEXN have been associated with dilated cardiomyopathy phenotypes, variants disrupting canonical splicing sites have not been frequently reported and have conflicting interpretations in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar; HGMD, Human Gene Mutation Database). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at