rs199476416
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5PP3BS1_SupportingBS2
The NM_032578.4(MYPN):c.3793G>A(p.Ala1265Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000186 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. 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. A1265P) has been classified as Uncertain significance.
Frequency
Consequence
NM_032578.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYPN | NM_032578.4 | c.3793G>A | p.Ala1265Thr | missense_variant, splice_region_variant | 19/20 | ENST00000358913.10 | |
LOC124902443 | XR_007062176.1 | n.128-2644C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYPN | ENST00000358913.10 | c.3793G>A | p.Ala1265Thr | missense_variant, splice_region_variant | 19/20 | 1 | NM_032578.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000658 AC: 10AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250930Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135598
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727226
GnomAD4 genome ? AF: 0.0000658 AC: 10AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74266
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Dilated cardiomyopathy 1KK Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1265 of the MYPN protein (p.Ala1265Thr). This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon. This variant is present in population databases (rs199476416, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 201893). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 | Feb 08, 2022 | The p.A1265T variant (also known as c.3793G>A), located in coding exon 18 of the MYPN gene, results from a G to A substitution at nucleotide position 3793. The alanine at codon 1265 is replaced by threonine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 18 and may have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at