rs749167943
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_144573.4(NEXN):āc.1A>Cā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000311 in 1,607,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
NEXN
NM_144573.4 start_lost
NM_144573.4 start_lost
Scores
5
6
5
Clinical Significance
Conservation
PhyloP100: 5.94
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 Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.1A>C | p.Met1? | start_lost | 2/13 | ENST00000334785.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.1A>C | p.Met1? | start_lost | 2/13 | 1 | NM_144573.4 | P3 | |
NEXN | ENST00000401035.7 | c.1A>C | p.Met1? | start_lost | 2/9 | 1 | |||
NEXN | ENST00000330010.12 | c.1A>C | p.Met1? | start_lost | 2/12 | 2 | A1 | ||
NEXN | ENST00000440324.5 | c.1A>C | p.Met1? | start_lost | 2/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247520Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134284
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GnomAD4 exome AF: 0.00000275 AC: 4AN: 1455334Hom.: 0 Cov.: 28 AF XY: 0.00000414 AC XY: 3AN XY: 724070
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
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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 submitter | clinical testing | Ambry Genetics | Jun 09, 2023 | The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the NEXN gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This amino acid position is highly conserved in available vertebrate species. Although biallelic loss of function alterations in NEXN have been associated with autosomal recessive NEXN-related cardiomyopathy, haploinsufficiency for NEXN has not been clearly established as a mechanism of disease for autosomal dominant NEXN-related cardiomyopathy. 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 | Jul 01, 2022 | This sequence change affects the initiator methionine of the NEXN mRNA. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs749167943, gnomAD 0.009%). 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: 519128). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
0.30
.;.;B;.
Vest4
0.90, 0.88
MutPred
Gain of catalytic residue at M1 (P = 0.1732);Gain of catalytic residue at M1 (P = 0.1732);Gain of catalytic residue at M1 (P = 0.1732);Gain of catalytic residue at M1 (P = 0.1732);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at