rs74350755
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_198271.5(LMOD3):c.1144C>T(p.Pro382Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,864 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0075 ( 17 hom., cov: 31)
Exomes 𝑓: 0.00073 ( 10 hom. )
Consequence
LMOD3
NM_198271.5 missense
NM_198271.5 missense
Scores
7
6
4
Clinical Significance
Conservation
PhyloP100: 10.0
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 Benign. Variant got -19 ACMG points.
PP3
?
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.021602124).
BP6
?
Variant 3-69119211-G-A is Benign according to our data. Variant chr3-69119211-G-A is described in ClinVar as [Benign]. Clinvar id is 475296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00753 (1146/152168) while in subpopulation AFR AF= 0.0247 (1026/41492). AF 95% confidence interval is 0.0235. There are 17 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 17 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMOD3 | NM_198271.5 | c.1144C>T | p.Pro382Ser | missense_variant | 2/3 | ENST00000420581.7 | |
LMOD3 | NM_001304418.3 | c.1144C>T | p.Pro382Ser | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMOD3 | ENST00000420581.7 | c.1144C>T | p.Pro382Ser | missense_variant | 2/3 | 1 | NM_198271.5 | P1 | |
LMOD3 | ENST00000475434.1 | c.1144C>T | p.Pro382Ser | missense_variant | 3/4 | 5 | P1 | ||
LMOD3 | ENST00000489031.5 | c.1144C>T | p.Pro382Ser | missense_variant | 3/4 | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00752 AC: 1143AN: 152050Hom.: 17 Cov.: 31
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00182 AC: 454AN: 248966Hom.: 8 AF XY: 0.00131 AC XY: 177AN XY: 135048
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GnomAD4 exome AF: 0.000731 AC: 1069AN: 1461696Hom.: 10 Cov.: 33 AF XY: 0.000616 AC XY: 448AN XY: 727128
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GnomAD4 genome ? AF: 0.00753 AC: 1146AN: 152168Hom.: 17 Cov.: 31 AF XY: 0.00702 AC XY: 522AN XY: 74394
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Asia WGS
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nemaline myopathy 10 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MVP
MPC
ClinPred
T
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