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

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

NEXN
NM_144573.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:12

Conservation

PhyloP100: 8.47
Variant links:
Genes affected
NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09270217 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
BS2
High AC in GnomAdExome4 at 109 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEXNNM_144573.4 linkuse as main transcriptc.1053+1G>A splice_donor_variant, intron_variant ENST00000334785.12 NP_653174.3 Q0ZGT2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEXNENST00000334785.12 linkuse as main transcriptc.1053+1G>A splice_donor_variant, intron_variant 1 NM_144573.4 ENSP00000333938.7 Q0ZGT2-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000324
AC:
8
AN:
246862
Hom.:
0
AF XY:
0.0000373
AC XY:
5
AN XY:
134144
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000723
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000747
AC:
109
AN:
1459720
Hom.:
0
Cov.:
31
AF XY:
0.0000633
AC XY:
46
AN XY:
726198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000926
Gnomad4 OTH exome
AF:
0.0000830
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
Uncertain significance, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingGeneDxOct 08, 2019Identified 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 providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 14, 2023This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 22, 2021- -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteApr 28, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 27, 2018The 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 submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 05, 2019- -
Hypertrophic cardiomyopathy 20 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyApr 06, 2022- -
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsSep 22, 2015- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2020The 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 submitterclinical testingPreventionGenetics, part of Exact SciencesAug 28, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.98
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517843; hg19: chr1-78395190; COSMIC: COSV57354778; COSMIC: COSV57354778; API