rs794729094

Positions:

• chr1-77942823-GAATT-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_144573.4(NEXN):​c.2026_*1del variant causes a frameshift, stop lost change. The variant allele was found at a frequency of 0.0000162 in 1,605,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NEXN NM_144573.4 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.88

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 -2 ACMG points.

• PM4: Stoplost variant in NM_144573.4 Downstream stopcodon found after 64 codons.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXN	NM_144573.4	c.2026_*1del		frameshift_variant, stop_lost	13/13	ENST00000334785.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXN	ENST00000334785.12	c.2026_*1del		frameshift_variant, stop_lost	13/13	1	NM_144573.4	P3
NEXN	ENST00000342754.5	c.1716+9_1716+12del		splice_donor_region_variant, intron_variant		1
NEXN	ENST00000330010.12	c.1834_*1del		frameshift_variant, stop_lost	12/12	2		A1
NEXN	ENST00000480732.2	n.1600_1603del		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000568 AC: 14 AN: 246376 Hom.: 0 AF XY: 0.0000523 AC XY: 7 AN XY: 133822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1453420 Hom.: 0 AF XY: 0.0000166 AC XY: 12 AN XY: 723448

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

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

Sep 11, 2017

The p.X676HisextX9 variant in NEXN has not been previously reported in individua ls with cardiomyopathy but has been identified in 13/34248 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs794729094). This variant deletes the stop codon, replaces it with a Histi dine and extends the protein by 8 amino acids. The impact of this change on prot ein function is unknown. NEXN variants have been described in individuals with D CM and HCM but they are rare and overall poorly studied. In summary, the clinica l significance of the p.X676HisextX9 variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2020

Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

The c.2026_*1delTAAT variant (also known as p.*676Hext*8) is located in coding exon 12 of the NEXN gene. This variant results from a deletion of 4 nucleotides from position 2026 into the 3' untranslated region. This alteration disrupts the stop codon of the NEXN gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 8 amino acids. The exact functional effect of the additional amino acids is unknown. 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

Nov 07, 2022

This variant is present in population databases (rs764404383, gnomAD 0.04%). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 201946). This variant has not been reported in the literature in individuals affected with NEXN-related conditions. This sequence change disrupts the translational stop signal of the NEXN mRNA. It is expected to extend the length of the NEXN protein by 8 additional amino acid residues. -

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: rs794729094; hg19: chr1-78408508;