rs397517843

Variant names:

• chr1-77929505-G-A
• rs397517843
• NM_144573.4:c.1053+1G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

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: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:12
• Conservation: PhyloP100: 8.47

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09319527 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000747 (109/1459720) while in subpopulation NFE AF= 0.0000926 (103/1111740). AF 95% confidence interval is 0.0000777. There are 0 homozygotes in gnomad4_exome. There are 46 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1053+1G>A		splice_donor_variant, intron_variant	Intron 9 of 12	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1053+1G>A		splice_donor_variant, intron_variant	Intron 9 of 12	1	NM_144573.4	ENSP00000333938.7

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

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

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:1 Uncertain:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Oct 08, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Pathogenic:1 Uncertain:1

Jul 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 47886). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 31514951). This variant is present in population databases (rs397517843, gnomAD 0.008%). 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). -

Oct 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Apr 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 28, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

Jun 05, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 20 Uncertain:1

Apr 06, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Sep 22, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEXN-related disorder Uncertain:1

Aug 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype Uncertain:1

Nov 17, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Other links and lift over

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