rs372011095
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 7P and 3B. PM1PM2PM5PP2BP4_ModerateBP6
The NM_170707.4(LMNA):āc.1376A>Gā(p.Asn459Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000464 in 1,574,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N459Y) has been classified as Pathogenic.
Frequency
Genomes: š 0.000039 ( 0 hom., cov: 32)
Exomes š: 0.000047 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
7
13
Clinical Significance
Conservation
PhyloP100: 3.78
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a domain LTD (size 117) in uniprot entity LMNA_HUMAN there are 96 pathogenic changes around while only 4 benign (96%) in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156136431-A-T is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.1749771).
BP6
Variant 1-156136432-A-G is Benign according to our data. Variant chr1-156136432-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178062.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1376A>G | p.Asn459Ser | missense_variant | 7/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.1376A>G | p.Asn459Ser | missense_variant | 7/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1376A>G | p.Asn459Ser | missense_variant | 7/12 | 1 | NM_170707.4 | ENSP00000357283 | P1 | |
| LMNA | ENST00000677389.1 | c.1376A>G | p.Asn459Ser | missense_variant | 7/10 | NM_005572.4 | ENSP00000503633 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000271 AC: 5AN: 184812Hom.: 0 AF XY: 0.0000101 AC XY: 1AN XY: 99130
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GnomAD4 exome AF: 0.0000471 AC: 67AN: 1422352Hom.: 0 Cov.: 33 AF XY: 0.0000483 AC XY: 34AN XY: 704352
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GnomAD4 genome 0.0000394 AC: 6AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2018 | A variant of uncertain significance has been identified in the LMNA gene. The N459S variant has been reported by Rodriguez et al. (2008) in a cohort of patients with cardiomyopathy, dysrhythmias, or cardiac progeria; however, phenotypic characteristics of the patient with the N459S variant was not defined. The N459S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The N459S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the N459S variant is located in the globular carboxy-terminal tail region of the LMNA gene. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 13, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 02, 2017 | The p.Asn459Ser variant (rs372011095) has been previously observed in a cohort of cardiomyopathy, dysrhythmias, or cardiac progeria patients (Rodriguez 2008), although no other specific clinical information is provided in relation to this patient population. This variant is also listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 6 out of 210,462 chromosomes). The asparagine at codon 459 is moderately conserved considering 11 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on LMNA protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). However, variants in nearby amino acids have been associated with Emery-Dreifuss muscular dystrophy (selected reference: Helbling-Leclerc 2002). This variant is also listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 178062). Thus, based on the available information, the clinical significance of the p.Asn459Ser variant cannot be determined with certainty. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 24, 2019 | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 06, 2023 | This missense variant replaces asparagine with serine at codon 459 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/216196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces asparagine with serine at codon 459 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/216196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2023 | The p.N459S variant (also known as c.1376A>G), located in coding exon 7 of the LMNA gene, results from an A to G substitution at nucleotide position 1376. The asparagine at codon 459 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 17, 2014 | Asn459Ser in exon 7 of LMNA: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals (cat, dog, walrus, seal, fox, and two bat species) have a ser ine (Ser) at this position despite high nearby amino acid conservation. It has a lso been identified in 1/4378 African American chromosomes by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs372011095). Additi onal computational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high l ikelihood of impact to the protein. Asn459Ser in exon 7 of LMNA (rs372011095; a llele frequency = 1/4378) ** - |
Charcot-Marie-Tooth disease type 2 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 03, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;.;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;N;N;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;T;D;D;T;D;D;T
Sift4G
Uncertain
D;T;D;D;T;T;T;D
Polyphen
B;B;B;.;.;B;.;.
Vest4
MVP
MPC
0.27
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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