rs397517846

Positions:

• chr1-77935971-TAGA-T
• chr1-77935971-TAGA-TAGAAGA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The ENST00000334785.12(NEXN):​c.1407_1409del​(p.Glu470del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,613,688 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I467I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: NEXN ENST00000334785.12 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 8.14

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.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000334785.12. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1407_1409del	p.Glu470del	inframe_deletion	11/13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1407_1409del	p.Glu470del	inframe_deletion	11/13	1	NM_144573.4	ENSP00000333938	P3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151884 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248888 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135154

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461686 Hom.: 1 AF XY: 0.000139 AC XY: 101 AN XY: 727134

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152002 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74292

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Identified in patients with DCM in the published literature (Pugh et al., 2014; Walsh et al., 2017); In-frame deletion of a single glutamic acid residue; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780) -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2019	- -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2022	This variant, c.1407_1409del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Glu470del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762929322, gnomAD 0.02%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 47890). 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. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2015	The p.Glu470del variant in NEXN has been identified by our laboratory in 1 infan t with DCM, 1 adult with LVNC (Pugh 2014), and 1 adult with HCM who carried a pa thogenic variant in another gene that was sufficient to explain the disease. Thi s variant has also been identified in 4/16472 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3975 17846). This variant is a deletion of a single amino acid at position 470 and do es not alter the protein reading-frame. It is unclear if this deletion will impa ct protein function. In summary, the clinical significance of the p.Glu470del va riant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: NEXN c.1407_1409delAGA (p.Glu470del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00012 in 1606714 control chromosomes, predominantly at a frequency of ~0.0003 within the African or African-American- and South Asian subpopulations in the gnomAD database (v4.0 dataset), including 1 homozygote. The observed variant frequency within African and South Asian control individuals in the gnomAD database is approximately 20-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEXN causing Dilated Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. c.1407_1409delAGA has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Pugh_2014, Walsh_2017, Pena-Pena_2021), however without providing strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 27532257, 32826072). ClinVar contains an entry for this variant (Variation ID: 47890). Based on the evidence outlined above, the variant was classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 9 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Dilated cardiomyopathy 1CC Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Medical Genetics Ghent, University of Ghent

Feb 09, 2016

This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server). The variant results in an inframe deletion of one amino acid and thus reduces the length of the protein. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2020

The c.1407_1409delAGA (p.E470del) alteration is located in exon 11 (coding exon 10) of the NEXN gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.1407 and c.1409, resulting in the deletion of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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: rs397517846; hg19: chr1-78401656;