1-77916110-AATG-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2

The NM_144573.4(NEXN):​c.7_9del​(p.Asp3del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000149 in 1,607,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β˜…β˜…).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NEXN
NM_144573.4 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_144573.4. Strenght limited to Supporting due to length of the change: 1aa.
BS2
High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEXNNM_144573.4 linkuse as main transcriptc.7_9del p.Asp3del inframe_deletion 2/13 ENST00000334785.12 NP_653174.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEXNENST00000334785.12 linkuse as main transcriptc.7_9del p.Asp3del inframe_deletion 2/131 NM_144573.4 ENSP00000333938 P3Q0ZGT2-1
NEXNENST00000401035.7 linkuse as main transcriptc.7_9del p.Asp3del inframe_deletion 2/91 ENSP00000383814
NEXNENST00000330010.12 linkuse as main transcriptc.7_9del p.Asp3del inframe_deletion 2/122 ENSP00000327363 A1Q0ZGT2-4
NEXNENST00000440324.5 linkuse as main transcriptc.7_9del p.Asp3del inframe_deletion 2/105 ENSP00000411902

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000202
AC:
5
AN:
247444
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
134230
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
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:
0.0000356
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1455528
Hom.:
0
AF XY:
0.0000110
AC XY:
8
AN XY:
724164
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000189
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 25, 2023The c.7_9delGAT variant (also known as p.D3del) is located in coding exon 1 of the NEXN gene. This variant results from an in-frame GAT deletion at nucleotide positions 7 to 9. This results in the in-frame deletion of an aspartic acid at codon 3. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 08, 2021This variant, c.7_9del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Asp3del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760463744, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NEXN-related conditions. ClinVar contains an entry for this variant (Variation ID: 518850). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs760463744; hg19: chr1-78381795; API