rs373546361
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_007078.3(LDB3):c.1132C>T(p.Pro378Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P378P) has been classified as Uncertain significance.
Frequency
Consequence
NM_007078.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.1132C>T | p.Pro378Ser | missense_variant | 9/14 | ENST00000361373.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.1132C>T | p.Pro378Ser | missense_variant | 9/14 | 1 | NM_007078.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248746Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135096
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460594Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726632
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74386
ClinVar
Submissions by phenotype
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2018 | This sequence change replaces proline with serine at codon 378 of the LDB3 protein (p.Pro378Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. The LDB3 gene has multiple clinically relevant transcripts. The p.Pro378Ser variant occurs in alternate transcript NM_007078.2, which corresponds to position c.*10577C>T in NM_001080116.1, the primary transcript listed in the Methods. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDB3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2022 | The p.P378S variant (also known as c.1132C>T), located in coding exon 8 of the LDB3 gene, results from a C to T substitution at nucleotide position 1132. The proline at codon 378 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at