rs1555123744
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000256.3(MYBPC3):c.220G>A(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A74V?) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.220G>A | p.Ala74Thr | missense_variant | 2/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.220G>A | p.Ala74Thr | missense_variant | 2/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.220G>A | p.Ala74Thr | missense_variant | 2/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.220G>A | p.Ala74Thr | missense_variant, NMD_transcript_variant | 2/27 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.00e-7 AC: 1AN: 1428328Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 707190
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 21, 2017 | This sequence change replaces alanine with threonine at codon 74 of the MYBPC3 protein (p.Ala74Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. In summary, this variant has uncertain impact on MYBPC3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a MYBPC3-related disease. This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at