chr17-10641341-CTTAAA-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PVS1PP5BS2_Supporting
The NM_002470.4(MYH3):c.1986_1990delTTTAA(p.Asn662LysfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002470.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.1986_1990delTTTAA | p.Asn662LysfsTer15 | frameshift_variant | Exon 18 of 41 | ENST00000583535.6 | NP_002461.2 | |
MYH3 | XM_011523870.4 | c.1986_1990delTTTAA | p.Asn662LysfsTer15 | frameshift_variant | Exon 18 of 41 | XP_011522172.1 | ||
MYH3 | XM_011523871.3 | c.1986_1990delTTTAA | p.Asn662LysfsTer15 | frameshift_variant | Exon 18 of 41 | XP_011522173.1 | ||
MYH3 | XM_047436127.1 | c.1986_1990delTTTAA | p.Asn662LysfsTer15 | frameshift_variant | Exon 20 of 43 | XP_047292083.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251478Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461030Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 726914
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Spondylocarpotarsal synostosis syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Group, University of Otago | Apr 09, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2020 | Observed as heterozygous variant in individual with spondylocarpotarsal synostosis syndrome; a second variant in MYH3 was not identified through whole exome sequencing, however whole genome sequencing was not available at the time of publication (Cameron-Christie et al., 2018); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29805041) - |
Contractures, pterygia, and variable skeletal fusions syndrome 1B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Provincial Medical Genetics Program of British Columbia, University of British Columbia | Jan 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at