rs397516045
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_000256.3(MYBPC3):c.3G>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,334 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3G>C | p.Met1? | start_lost | Exon 1 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.3G>C | p.Met1? | start_lost | Exon 1 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.3G>C | non_coding_transcript_exon_variant | Exon 1 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000433 AC: 1AN: 231038Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126104
GnomAD4 exome AF: 0.00000277 AC: 4AN: 1443334Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2AN XY: 717890
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Reported in association with cardiomyopathy (PMID: 25611685); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 28679633, 30297972, 37652022, 29524613, 25611685) -
not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Hypertrophic cardiomyopathy Uncertain:1
This sequence change affects the initiator methionine of the MYBPC3 mRNA. The next in-frame methionine is located at codon 103. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 29524613). ClinVar contains an entry for this variant (Variation ID: 42747). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at