chr10-86668785-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2
The NM_007078.3(LDB3):c.93+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,459,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007078.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.93+1G>T | splice_donor_variant, intron_variant | Intron 2 of 13 | ENST00000361373.9 | NP_009009.1 | ||
LDB3 | NM_001368067.1 | c.93+1G>T | splice_donor_variant, intron_variant | Intron 2 of 8 | ENST00000263066.11 | NP_001354996.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.93+1G>T | splice_donor_variant, intron_variant | Intron 2 of 13 | 1 | NM_007078.3 | ENSP00000355296.3 | |||
LDB3 | ENST00000263066.11 | c.93+1G>T | splice_donor_variant, intron_variant | Intron 2 of 8 | 1 | NM_001368067.1 | ENSP00000263066.7 | |||
ENSG00000289258 | ENST00000443292.2 | c.1602+1G>T | splice_donor_variant, intron_variant | Intron 12 of 17 | 1 | ENSP00000393132.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459818Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726310
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Myofibrillar myopathy 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 17, 2024 | The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.93+1G>T in the primary transcript. This sequence change affects a donor splice site in intron 2 of the LDB3 gene. It is expected to disrupt RNA splicing on both transcripts. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547); however, loss-of-function variants in LDB3 are only known to be pathogenic in the alternate transcript (PMID: 36253531). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179706). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 01, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The 93+1G>T var iant in LDB3 has not been previously reported in any other families with cardiom yopathy or myopathy. It was also absent from large population studies. This vari ant occurs in the invariant region (+/- 1, 2) of the splice consensus sequence a nd is predicted to cause altered splicing leading to an abnormal or absent prote in. Mouse studies indicate that the spectrum of phenotypes resulting from homozy gous loss-of-function (LOF) of LDB3 include DCM and congenital myopathy (Zhou 20 01, Zheng 2009), however heterozygous LOF has not been well studied. Our laborat ory has previously identified 5 predicted LOF variants that are also expected to lead to an abnormal or absent protein; 1 was identified in a heterozygous adult with VT and SCA, 1 was identified in a heterozygous infant with DCM, 3 were ide ntified in compound heterozygous or homozygous infant with DCM +/- noncompaction . In summary, the predicted impact to the protein increases the likelihood that this variant is pathogenic, but additional studies are required to fully establi sh its clinical significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at