rs751254270
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_007078.3(LDB3):c.443G>A(p.Arg148Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R148W) has been classified as Uncertain significance.
Frequency
Consequence
NM_007078.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.443G>A | p.Arg148Gln | missense_variant | 5/14 | ENST00000361373.9 | |
LDB3 | NM_001368067.1 | c.321+1400G>A | intron_variant | ENST00000263066.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.443G>A | p.Arg148Gln | missense_variant | 5/14 | 1 | NM_007078.3 | P4 | |
LDB3 | ENST00000263066.11 | c.321+1400G>A | intron_variant | 1 | NM_001368067.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000806 AC: 2AN: 248000Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134586
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460650Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 726670
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Located in an alternate transcript of the LDB3 gene; This variant is associated with the following publications: (PMID: 27535533) - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 26, 2021 | - - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 191695). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the LDB3 protein (p.Arg148Gln). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1400G>A in the primary transcript. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at