rs201786090
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2
The NM_007078.3(LDB3):c.160G>A(p.Gly54Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
LDB3
NM_007078.3 missense
NM_007078.3 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 10.0
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 Likely_benign. Variant got -4 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.789
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000525 (8/152254) while in subpopulation EAS AF= 0.000386 (2/5182). AF 95% confidence interval is 0.0000683. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.160G>A | p.Gly54Ser | missense_variant | Exon 3 of 14 | 1 | NM_007078.3 | ENSP00000355296.3 | ||
LDB3 | ENST00000263066.11 | c.160G>A | p.Gly54Ser | missense_variant | Exon 3 of 9 | 1 | NM_001368067.1 | ENSP00000263066.7 | ||
ENSG00000289258 | ENST00000443292.2 | c.1669G>A | p.Gly557Ser | missense_variant | Exon 13 of 18 | 1 | ENSP00000393132.2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152136Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251422Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135896
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727232
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GnomAD4 genome AF: 0.0000525 AC: 8AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74442
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 10, 2013 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 17, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 54 of the LDB3 protein (p.Gly54Ser). This variant is present in population databases (rs201786090, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic or dilated cardiomyopathy (PMID: 24730657, 31983221, 32880476). ClinVar contains an entry for this variant (Variation ID: 93526). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 | Nov 09, 2021 | The p.G54S variant (also known as c.160G>A), located in coding exon 2 of the LDB3 gene, results from a G to A substitution at nucleotide position 160. The glycine at codon 54 is replaced by serine, an amino acid with similar properties. This variant was reported in an individual with severe hypertrophic cardiomyopathy (HCM) and in two dilated cardiomyopathy (DCM) cases with limited details (Fratev F et al. J Chem Inf Model, 2014 May;54:1524-36; Mazzarotto F et al. Circulation, 2020 02;141:387-398; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M;M;.;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D;D;.;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;.;D;D;D
Vest4
MVP
MPC
ClinPred
D
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