rs730880643
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_000256.3(MYBPC3):c.1543_1545delAAC(p.Asn515del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000186 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000256.3 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1543_1545delAAC | p.Asn515del | conservative_inframe_deletion | Exon 17 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.1543_1545delAAC | p.Asn515del | conservative_inframe_deletion | Exon 16 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.1543_1545delAAC | non_coding_transcript_exon_variant | Exon 17 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249246Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135216
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461694Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727132
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
This variant causes an in-frame deletion of one amino acid in exon 17 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 33495597, 33892289) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has been identified in 3/280634 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This variant, c.1543_1545del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Asn515del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs730880643, gnomAD 0.004%). This variant has been observed in individuals with clinical features of dilated cardiomyopathy and/or clinical features of hypertrophic cardiomyopathy (PMID: 21750094, 33495597, 33892289, 35653365, 37466024; internal data). ClinVar contains an entry for this variant (Variation ID: 181070). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Left ventricular noncompaction 10 Uncertain:1
Criteria applied: PS4_MOD,PM2_SUP,PM4_SUP -
Cardiomyopathy Uncertain:1
This variant causes an in-frame deletion of one amino acid in exon 17 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 33495597, 33892289) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has been identified in 3/280634 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Observed with a second variant on the opposite allele (in trans) in a patient with HCM diagnosed in early childhood; however, detailed cardiac information was not provided (PMID: 30009132); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21750094, 33892289, 30009132, 33495597, 35653365) -
Cardiovascular phenotype Uncertain:1
The c.1543_1545delAAC variant (also known as p.N515del) is located in coding exon 17 of the MYBPC3 gene. This variant results from an in-frame AAC deletion at nucleotide positions 1543 to 1545. This results in the in-frame deletion of an asparagine at codon 515. This alteration has been reported in a subject with dilated cardiomyopathy and has been seen in a mitochondrial disorders cohort (Waldmüller S et al, Eur J Heart Failure. 2011 Nov;13:1185-92; Puusepp S et al, Mol Genet Mteb Rep. 2018 Jun;15:80-89).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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