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

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDB3
NM_007078.3 splice_donor, intron

Scores

4
1
2
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 10-86668785-G-T is Pathogenic according to our data. Variant chr10-86668785-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179706.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
BS2
High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDB3NM_007078.3 linkc.93+1G>T splice_donor_variant, intron_variant Intron 2 of 13 ENST00000361373.9 NP_009009.1 O75112-1
LDB3NM_001368067.1 linkc.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
LDB3ENST00000361373.9 linkc.93+1G>T splice_donor_variant, intron_variant Intron 2 of 13 1 NM_007078.3 ENSP00000355296.3 O75112-1
LDB3ENST00000263066.11 linkc.93+1G>T splice_donor_variant, intron_variant Intron 2 of 8 1 NM_001368067.1 ENSP00000263066.7 O75112-6
ENSG00000289258ENST00000443292.2 linkc.1602+1G>T splice_donor_variant, intron_variant Intron 12 of 17 1 ENSP00000393132.2 C9JWU6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1459818
Hom.:
0
Cov.:
31
AF XY:
0.00000826
AC XY:
6
AN XY:
726310
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Myofibrillar myopathy 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 17, 2024The 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 01, 2014Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Benign
0.64
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.20
Position offset: -2
DS_DL_spliceai
0.99
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727505066; hg19: chr10-88428542; API