rs745957045
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_198271.5(LMOD3):c.1249A>T(p.Ile417Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
LMOD3
NM_198271.5 missense
NM_198271.5 missense
Scores
1
2
15
Clinical Significance
Conservation
PhyloP100: 3.85
Genes affected
LMOD3 (HGNC:6649): (leiomodin 3) The protein encoded by this gene is a member of the leiomodin family of proteins. This protein contains three actin-binding domains, a tropomyosin domain, a leucine-rich repeat domain, and a Wiskott-Aldrich syndrome protein homology 2 domain (WH2). Localization of this protein to the pointed ends of thin filaments has been observed, and there is evidence that this protein acts as a catalyst of actin nucleation, and is important to the organization of sarcomeric thin filaments in skeletal muscles. Mutations in this gene have been associated as one cause of Nemaline myopathy, as other genes have also been linked to this disorder. Nemaline myopathy is a disorder characterized by nonprogressive generalized muscle weakness and protein inclusions (nemaline bodies) in skeletal myofibers. Patients with mutations in this gene often present with a severe congenital form of the disorder. [provided by RefSeq, Jan 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2285637).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMOD3 | NM_198271.5 | c.1249A>T | p.Ile417Leu | missense_variant | 2/3 | ENST00000420581.7 | |
LMOD3 | NM_001304418.3 | c.1249A>T | p.Ile417Leu | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMOD3 | ENST00000420581.7 | c.1249A>T | p.Ile417Leu | missense_variant | 2/3 | 1 | NM_198271.5 | P1 | |
LMOD3 | ENST00000475434.1 | c.1249A>T | p.Ile417Leu | missense_variant | 3/4 | 5 | P1 | ||
LMOD3 | ENST00000489031.5 | c.1249A>T | p.Ile417Leu | missense_variant | 3/4 | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152036Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249130Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135148
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461702Hom.: 0 Cov.: 33 AF XY: 0.0000316 AC XY: 23AN XY: 727132
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152036Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74264
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nemaline myopathy 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 417 of the LMOD3 protein (p.Ile417Leu). This variant is present in population databases (rs745957045, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LMOD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 580464). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | The c.1249A>T (p.I417L) alteration is located in exon 2 (coding exon 2) of the LMOD3 gene. This alteration results from a A to T substitution at nucleotide position 1249, causing the isoleucine (I) at amino acid position 417 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;B
Vest4
MutPred
Loss of methylation at K414 (P = 0.0438);Loss of methylation at K414 (P = 0.0438);Loss of methylation at K414 (P = 0.0438);
MVP
MPC
ClinPred
T
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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