chr1-77935986-CAAG-C

Variant names:

• chr1-77935986-CAAG-C
• rs794729091
• NM_144573.4:c.1419_1421delAAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_144573.4(NEXN):​c.1419_1421delAAG​(p.Arg474del) variant causes a disruptive 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). Synonymous variant affecting the same amino acid position (i.e. R473R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NEXN NM_144573.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 2.09
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1CC

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 20

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_144573.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 1-77935986-CAAG-C is Benign according to our data. Variant chr1-77935986-CAAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201940.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000132 (20/151988) while in subpopulation NFE AF = 0.000221 (15/68004). AF 95% confidence interval is 0.000135. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1419_1421delAAG	p.Arg474del	disruptive_inframe_deletion	Exon 11 of 13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1419_1421delAAG	p.Arg474del	disruptive_inframe_deletion	Exon 11 of 13	1	NM_144573.4	ENSP00000333938.7

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151988 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000173 AC: 43 AN: 249020 AF XY: 0.000207

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 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.: 0 AF XY: 0.000138 AC XY: 100 AN XY: 727132

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86180

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111958

Other (OTH) AF: 0.000182 AC: 11 AN: 60386

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151988 Hom.: 0 Cov.: 33 AF XY: 0.0000943 AC XY: 7 AN XY: 74236

African (AFR) AF: 0.0000725 AC: 3 AN: 41354

American (AMR) AF: 0.0000656 AC: 1 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000170

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Apr 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 19, 2024

Clinical Genomics Laboratory, Stanford Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NEXN c.1419_1421del (p.Arg475del) variant identified in this individual was previously classified as a variant of uncertain significance on the original report issued 06/05/2023. Since the original reporting of this variant, updated population data indicates that this variant is present in the population at an allele frequency higher than expected for a pathogenic variant. This variant has been identified in 7/6084 Middle Eastern chromosomes (196/1613672 chromosomes overall) by the Genome Aggregation Database v4.1.0 (http://gnomad.broadinstitute.org/). This additional information provides sufficient evidence to update the classification of the NEXN c.1419_1421del (p.Arg475del) variant to likely benign. -

Jan 23, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 22, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 01, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial dilated cardiomyopathy Uncertain:1

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEXN-related disorder Uncertain:1

Jul 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 23, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.1
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs794729091; hg19: chr1-78401671;