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rs372532824

chr1-77917989-G-Achr1-77917989-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_144573.4(NEXN):c.249G>A(p.Glu83=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,613,190 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

NEXN
NM_144573.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -0.00200
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-77917989-G-A is Benign according to our data. Variant chr1-77917989-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178102.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=7}. Variant chr1-77917989-G-A is described in Lovd as [Likely_benign]. Variant chr1-77917989-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.002 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEXNNM_144573.4 linkuse as main transcriptc.249G>A p.Glu83= synonymous_variant 4/13 ENST00000334785.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEXNENST00000334785.12 linkuse as main transcriptc.249G>A p.Glu83= synonymous_variant 4/131 NM_144573.4 P3Q0ZGT2-1
NEXNENST00000401035.7 linkuse as main transcriptc.57G>A p.Glu19= synonymous_variant 3/91
NEXNENST00000330010.12 linkuse as main transcriptc.57G>A p.Glu19= synonymous_variant 3/122 A1Q0ZGT2-4
NEXNENST00000440324.5 linkuse as main transcriptc.249G>A p.Glu83= synonymous_variant 4/105

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000602
AC:
15
AN:
249374
Hom.:
0
AF XY:
0.0000665
AC XY:
9
AN XY:
135320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000397
AC:
58
AN:
1461042
Hom.:
0
Cov.:
31
AF XY:
0.0000385
AC XY:
28
AN XY:
726866
show subpopulations
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:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000441
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000793
Asia WGS
AF:
0.000289
AC:
1
AN:
3476
EpiCase
AF:
0.00
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 21, 2021- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022NEXN: BP4, BP7 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 04, 2015- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 19, 2012Glu83Glu in Exon 04 of NEXN: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence. It has been identified in 0.015% (1/6530) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS). Glu83Glu in Exon 04 of NEXN (allele frequency =1/6530)** -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJan 24, 2022- -
NEXN-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 02, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 03, 2022This 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. -
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeOct 29, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
Cadd
Benign
3.9
Dann
Benign
0.39

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.

Other links and lift over

dbSNP: rs372532824; hg19: chr1-78383674; API