rs727504874

Positions:

• chr1-77933406-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000334785.12(NEXN):​c.1181_1182del​(p.Glu394GlyfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T393T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEXN ENST00000334785.12 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1181_1182del	p.Glu394GlyfsTer6	frameshift_variant	10/13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1181_1182del	p.Glu394GlyfsTer6	frameshift_variant	10/13	1	NM_144573.4	ENSP00000333938	P3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 22, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Glu394fs va riant in NEXN has not been previously reported in individuals with cardiomyopath y and data from large population studies is insufficient to assess its frequency . This frameshift variant is predicted to alter the protein?s amino acid sequenc e beginning at position 394 and lead to a premature termination codon 6 amino ac ids downstream. This alteration is then predicted to lead to a truncated or abse nt protein. Although the severe nature of the change increases the likelihood th at the variant is pathogenic, the NEXN gene has not been widely studied and the spectrum of variants leading to disease is not well-defined. Loss-of-function o f NEXN has been shown to cause DCM in animal models, however, it remains unclear if one or both copies of the gene need to be affected to cause disease. In summ ary, additional information is needed to fully assess the clinical significance of this variant. -

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: rs727504874; hg19: chr1-78399091;