rs727503230
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001145809.2(MYH14):c.5959C>T(p.Arg1987Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001145809.2 stop_gained, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH14 | NM_001145809.2 | c.5959C>T | p.Arg1987Ter | stop_gained, splice_region_variant | 42/43 | ENST00000642316.2 | |
MYH14 | NM_001077186.2 | c.5860C>T | p.Arg1954Ter | stop_gained, splice_region_variant | 41/42 | ||
MYH14 | NM_024729.4 | c.5836C>T | p.Arg1946Ter | stop_gained, splice_region_variant | 40/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH14 | ENST00000642316.2 | c.5959C>T | p.Arg1987Ter | stop_gained, splice_region_variant | 42/43 | NM_001145809.2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461532Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727068
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2023 | Variant summary: MYH14 c.5836C>T (p.Arg1946X) results in a premature termination codon which is predicted to cause a truncation of the encoded protein, but is not expected to result in nonsense mediated decay. The variant was absent in 249144 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5836C>T in individuals affected with Autosomal Dominant Deafness and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 25, 2013 | Variant classified as Uncertain Significance - Favor Pathogenic. The Arg1987X va riant in MYH14 has not been previously reported in individuals with hearing loss or in large population studies. This nonsense variant leads to a premature term ination codon at position 1987 which is 50 amino acid positions upstream of the canonical termination codon. However, the truncation occurs within 50 nucleotide s of the terminal exon-exon junction, and nonsense mediated decay may not occur (Zhang 1998). Therefore, the impact of the variant on the normal function of the protein cannot be predicted. In summary, the clinical significance of this vari ant cannot be determined with certainty; however due to the fact that the varian t is predicted to result in a truncated protein, we would lean towards a more li kely pathogenic role. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at