rs750076188

Variant names:

• chr1-77933402-C-T
• rs750076188
• NM_144573.4:c.1174C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_144573.4(NEXN):​c.1174C>T​(p.Arg392*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,612,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: NEXN NM_144573.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7
• Conservation: PhyloP100: 3.56

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-77933402-C-T is Pathogenic according to our data. Variant chr1-77933402-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229051.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=6, Pathogenic=1}. Variant chr1-77933402-C-T is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1174C>T	p.Arg392*	stop_gained	Exon 10 of 13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1174C>T	p.Arg392*	stop_gained	Exon 10 of 13	1	NM_144573.4	ENSP00000333938.7

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151768 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248708 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135006

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: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1460656 Hom.: 0 Cov.: 30 AF XY: 0.0000440 AC XY: 32 AN XY: 726630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151768 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74088

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.0000950

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Nov 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg392*) in the NEXN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXN are known to be pathogenic (PMID: 32058062, 32814711, 32870709, 33949776). This variant is present in population databases (rs750076188, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546, 33949776). ClinVar contains an entry for this variant (Variation ID: 229051). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEXN p.Arg392X variant was identified in a study performing NGS on 639 patients with dilated cardiomyopathy (Haas_2014_PMID:25163546). It was not identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs750076188) and Clinvar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 7 of 280056 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 6 of 128186 chromosomes (freq: 0.000047) and European (Finnish) in 1 of 25012 chromosomes (freq: 0.00004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Other or South Asian populations. The p.Arg392X variant leads to a premature stop codon at position 392 which is predicted to lead to a truncated or absent protein and loss of function. The role of NEXN loss of function variants in disease is still unclear, however NEXN knock-out mice studies display a cardiomyopathy phenotype (Aherrahrou_2016_PMID:26659360). Further, MutationTaster predicts the variant to be disease-causing (prob: 1). 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. -

Jan 19, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:1

Nov 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in NEXN is a nonsense variant predicted to cause a premature stop codon, p.(Arg392*), in biologically relevant exon 10/16 leading to nonsense-mediated decay in a gene in which there is emerging evidence for loss of function as the mechanism of disease (PMID: 19881492, 26659360, 31983221, 32058062, 32635769, 32814711, 32870709, 33949776, 35166435). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.005% (6/128,186 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy (DCM). This variant has been reported heterozygous in at least eight probands with DCM (including one proband with a pathogenic FLNC variant), at least one proband with hypertrophic cardiomyopathy and one proband with an unknown cardiomyopathy (PMID: 25163546, 28008423, 30847666, 31983221, 32880476, 35581137, ClinVar: SCV001572576.1, SCV001366672.2). This variant has been detected homozygous in at least one foetus with hydrops and abnormal cardiac function (PMID: 33949776). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Moderate, PS4_Moderate, PM2_Supporting, PM3_Supporting. -

not specified Uncertain:1

Apr 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg392X v ariant in NEXN has not been previously reported in individuals with cardiomyopat hy, but has been identified in 1/64806 of European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 392, which is predicted to l ead to a truncated or absent protein. Although the severe nature of this change increases the likelihood that the variant is pathogenic, the NEXN gene has not b een widely studied and the spectrum of variants leading to disease is not well-d efined. Loss of NEXN function has been shown to cause DCM in zebrafish (Hassel 2 009, Wang 2010) and loss of function variants have been identified in individual s with a range of cardiomyopathies (LMM unpublished data); however, it remains u nclear if one or both copies of the gene need to be affected to cause disease. I n summary, while there is some suspicion for a pathogenic role, the clinical sig nificance of the p.Arg392X variant is uncertain. -

Dilated cardiomyopathy 1CC Uncertain:1

May 23, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP5. -

Hypertrophic cardiomyopathy Uncertain:1

Feb 26, 2021

Loeys Lab, Universiteit Antwerpen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift variant in the NEXN gene (p.(Arg392*)). This variant is present in population databases with a prevalence of 7/276332in GnomAD. Loss of function of NEXN caused DCM in zebrafish (PMID: 19881492). This variant has not been reported in the literature. We identified the variant in 3 unrelated patients: two patients with DCM and one patient with HCM. In the HCM family a second individual with HCM also carried the variant (limited data on segregation:PP1weak). No segregation data are available for the DCM families. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met). -

Cardiovascular phenotype Uncertain:1

Aug 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R392* variant (also known as c.1174C>T), located in coding exon 9 of the NEXN gene, results from a C to T substitution at nucleotide position 1174. This changes the amino acid from an arginine to a stop codon within coding exon 9. This variant has been detected in the homozygous state in an individual with severe early-onset and fatal dilated cardiomyopathy (DCM) whose heterozygous parents were unaffected (Bruyndonckx L et al. Am J Med Genet A, 2021 08;185:2464-2470). This alteration has also been detected (presumed heterozygous) in individuals from DCM and hypertrophic cardiomyopathy cohorts; however, clinical details were limited and additional alterations in cardiac-related genes were identified in some cases (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; Begay RL et al. JACC Basic Transl Sci. 2016 Aug;1(5):344-359; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487; Boen HM et al. J Heart Lung Transplant. 2022 Sep;41(9):1218-1227). Although biallelic loss of function alterations in NEXN have been associated with autosomal recessive NEXN-related cardiomyopathy, haploinsufficiency for NEXN has not been clearly established as a mechanism of disease for autosomal dominant NEXN-related cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive NEXN-related cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant NEXN-related cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.41
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs750076188; hg19: chr1-78399087;