Variant rs794729091 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBS1_SupportingBS2

The ENST00000334785.12(NEXN):c.1419_1421del(p.Arg475del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

NEXN
ENST00000334785.12 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 2.09

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]

NEXN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000334785.12. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00012 (176/1461684) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 100 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4 linkuse as main transcript	c.1419_1421del	p.Arg475del	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 linkuse as main transcript	c.1419_1421del	p.Arg475del	inframe_deletion	11/13	1	NM_144573.4	ENSP00000333938	P3	Q0ZGT2-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

249020

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000120

AC:

176

AN:

1461684

Hom.:

AF XY:

0.000138

AC XY:

100

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000132

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000170

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	Reported in an individual with DCM (Gigli et al., 2019); described as c.1416_1418delAAG (p.Arg475del); In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31514951) -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 22, 2013

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Arg474del (c.1419_1421delAAG) This variant is novel. This variant is located in exon 11 (coding exon 10) of the NEXN gene. The variant results from an in-frame AAG deletion between nucleotide position 1419 and 1421. This results in the deletion of an arginine residue at codon 474. The arginine at codon 474 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 474 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 8/1/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 8/1/13). Ambry genetics did not include internal control data. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 01, 2019

- -

Primary familial dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

NEXN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2024

The NEXN c.1419_1421delAAG variant is predicted to result in an in-frame deletion (p.Arg475del). This variant was reported in individuals with dilated cardiomyopathy or sudden death; however, no additional studies were performed to help assess the pathogenicity of this variant (Scheiper et al. 2018. PubMed ID: 30415094; Online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; described as c.1416_1418delAAG in Online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/201940). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This variant, c.1419_1421del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Arg475del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766608869, gnomAD 0.02%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 31514951). ClinVar contains an entry for this variant (Variation ID: 201940). 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. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over