rs201763096

Positions:

chr1-77929446-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144573.4(NEXN):c.995A>C(p.Glu332Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00335 in 1,613,478 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 28 hom. )

Consequence

NEXN
NM_144573.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:17

Conservation

PhyloP100: 4.10

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00764665).

BP6

Variant 1-77929446-A-C is Benign according to our data. Variant chr1-77929446-A-C is described in ClinVar as [Benign]. Clinvar id is 47915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-77929446-A-C is described in Lovd as [Benign]. Variant chr1-77929446-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00289 (440/152322) while in subpopulation SAS AF= 0.0128 (62/4828). AF 95% confidence interval is 0.0103. There are 2 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4 linkuse as main transcript	c.995A>C	p.Glu332Ala	missense_variant	9/13	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.995A>C	p.Glu332Ala	missense_variant	9/13	1	NM_144573.4	ENSP00000333938	P3	Q0ZGT2-1

Frequencies

GnomAD3 genomes

AF:

0.00288

AC:

438

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.00688

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00306

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00427

AC:

1052

AN:

246598

Hom.:

AF XY:

0.00497

AC XY:

666

AN XY:

134022

show subpopulations

Gnomad AFR exome

AF:

0.000970

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00299

Gnomad EAS exome

AF:

0.000223

Gnomad SAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.00761

Gnomad NFE exome

AF:

0.00313

Gnomad OTH exome

AF:

0.00398

GnomAD4 exome

AF:

0.00340

AC:

4964

AN:

1461156

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2695

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00276

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.00560

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00363

GnomAD4 genome

AF:

0.00289

AC:

440

AN:

152322

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0128

Gnomad4 FIN

AF:

0.00688

Gnomad4 NFE

AF:

0.00306

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00310

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00108

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00397

AC:

480

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00302

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 08, 2015	p.Glu332Ala in exon 9 of NEXN: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (207/16506) of South Asian chro mosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs201763096). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 01, 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.Glu332Ala (c.995 A>C) in the NEXN gene. This variant is reviewed in detail below. Recently, missense mutations that cause defective interaction between nexilin and alpha-actin have been described in HCM. Nexilin (NEXN) is a cardiac Z-disc protein that has a crucial function to protect cardiac Z-discs from forces generated within the sarcomere. The Z-disc complex is located at either end of the contractile unit of the striated muscle and links titin and actin filaments from opposing sarcomere halves in a lattice connected by ?-actinin. The Z-discs provide a backbone for the insertions of actin-based thin filaments and represent a key interface between the contractile apparatus and the cytoskeleton. In addition, the complex molecular network of Z-disc proteins is pivotal for reception, transduction, and transmission of mechanical and biochemical signals Hassel et al. (2009) found that nexilin is highly abundant in the heart and skeletal muscle and is located specifically to the Z-disc; loss of nexilin in zebrafish led to perturbed Z-disc stability and heart failure. They identified one deletion and two missense mutations in NEXN in a large cohort of patients with dilated cardiomyopathy. Wang et al. (2010) Reported variants in NEXN to cause HCM. They screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease and identified two missense variants. The variant p. Glu332Ala has not been published in the literature. In silico analysis with PolyPhen-2 predicts the variant to be is benign. Analysis with Mutation Taster predicts it to be disease causing with a score of 2.92. The 332 at codon is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons. Gu332Ala results in a non-conservative amino acid substitution of a negtatively-charged Glutamic acid residue with a non-polar Alanine residue at a positive that is class conserved across species. In total the variant has been seen in 24/11896 published controls and individuals from publicly available population datasets. GeneDx did not provide laboratory control data. The NHLBI Exome Sequencing Project dataset identified this variant in 20/8186 alleles from individuals of European ancestry and 4/3710 alleles from individual of African American ancestry, which currently includes variant calls on ~6000 Caucasian and African American individuals (as of 5/15/13). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 5/15/13). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2016	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	NEXN: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 07, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 22, 2019

- -

Premature ventricular contraction

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 25, 2019

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, no assertion criteria provided

research

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2016

This alteration is classified as 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T;T;T

MetaRNN

Benign

0.0076

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.1

.;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.0

D;N;N;D

REVEL

Benign

0.16

Sift

Uncertain

0.027

D;D;D;D

Sift4G

Uncertain

0.010

D;T;T;T

Polyphen

0.0

.;.;B;.

Vest4

0.22, 0.24

MVP

0.86

MPC

0.049

ClinPred

0.068

GERP RS

5.0

Varity_R

0.14

gMVP

0.12

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