rs397517847

Positions:

• chr1-77936028-C-G
• chr1-77936028-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144573.4(NEXN):​c.1457C>G​(p.Ala486Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NEXN NM_144573.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.11

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXN	NM_144573.4	c.1457C>G	p.Ala486Gly	missense_variant	11/13	ENST00000334785.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXN	ENST00000334785.12	c.1457C>G	p.Ala486Gly	missense_variant	11/13	1	NM_144573.4	P3
NEXN	ENST00000342754.5	c.1157C>G	p.Ala386Gly	missense_variant	7/10	1
NEXN	ENST00000330010.12	c.1265C>G	p.Ala422Gly	missense_variant	10/12	2		A1
NEXN	ENST00000480732.2	n.1031C>G		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460510 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726636

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: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 13, 2019

The p.Ala486Gly variant in NEXN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2019

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 47892; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27532257) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The p.A486G variant (also known as c.1457C>G), located in coding exon 10 of the NEXN gene, results from a C to G substitution at nucleotide position 1457. The alanine at codon 486 is replaced by glycine, an amino acid with similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy cohorts (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2018

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 47892). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 486 of the NEXN protein (p.Ala486Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.37	T;T
Polyphen		0.97	.;D
Vest4		0.46
MutPred		0.20		.;Gain of relative solvent accessibility (P = 0.0522);
MVP		0.74
MPC		0.16
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517847; hg19: chr1-78401713;