chr10-86679433-G-A
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
Consequence
NM_007078.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
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
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251422Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135896
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727232
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74442
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Myofibrillar myopathy 4 Uncertain:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at