rs557849165
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002470.4(MYH3):c.-9+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 152,282 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_002470.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.-9+1G>A | splice_donor_variant, intron_variant | ENST00000583535.6 | NP_002461.2 | |||
MYH3 | XM_011523870.4 | c.-9+1G>A | splice_donor_variant, intron_variant | XP_011522172.1 | ||||
MYH3 | XM_011523871.3 | c.-9+1G>A | splice_donor_variant, intron_variant | XP_011522173.1 | ||||
MYH3 | XM_047436127.1 | c.-9+1G>A | splice_donor_variant, intron_variant | XP_047292083.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.-9+1G>A | splice_donor_variant, intron_variant | 5 | NM_002470.4 | ENSP00000464317.1 | ||||
MYH3 | ENST00000582580.1 | n.80+1G>A | splice_donor_variant, intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00114 AC: 173AN: 152164Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 80Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 60
GnomAD4 genome AF: 0.00114 AC: 173AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97AN XY: 74472
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2024 | RNA studies demonstrate a damaging effect resulting in reduction of translational efficiency (PMID: 29805041); Reported with a second MYH3 variant in patients with complex skeletal anomalies (PMID: 35169139, 37273706); This variant is associated with the following publications: (PMID: 32902138, 34440395, 33726816, Sergi2022[casereport], 34204301, 38444278, 29805041, 37273706, 35169139) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 15, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | MYH3: PM3:Strong, PM2:Supporting, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This variant occurs in a non-coding region of the MYH3 gene. It does not change the encoded amino acid sequence of the MYH3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs557849165, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with clinical features of autosomal recessive MYH3-related conditions (PMID: 29805041, 32902138; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 587706). Studies have shown that this variant alters MYH3 gene expression (PMID: 29805041). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 29805041). For these reasons, this variant has been classified as Pathogenic. - |
MYH3-related disorder Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 08, 2024 | The MYH3 c.-9+1G>A variant is located in the 5' untranslated region. This variant has been reported in the compound heterozygous state in at least six individuals from three different families with autosomal recessive spondylocarpotarsal synostosis syndrome (Cameron-Christie et al 2018. PubMed ID: 29805041). This variant was also detected in the compound heterozygous state in patients with MYH3-associated conditions (Hakonen et al. 2020. PubMed ID: 32902138; Dahan-Oliel et al. 2021. PubMed ID: 34440395; Zhao et al. 2022. PubMed ID: 35169139). In addition, functional evidence supports that this variant results in aberrant splicing and reduced translational efficiency (Cameron-Christie et al 2018. PubMed ID: 29805041). Although this variant has an allele frequency up to 1.1% in Finnish Europeans, this variant is suggested to be a hypomorphic allele. In summary, this variant is interpreted as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 23, 2022 | Variant summary: MYH3 c.-9+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in loss of part of 5'-UTR sequence (Cameron-Christie_2018). The variant allele was found at a frequency of 0.0027 in 31404 control chromosomes. c.-9+1G>A has been reported in the literature and found in our internal database in individuals affected with MYH3-Related Disorders in compound heterozygous or heterozygous status. These reports do not provide unequivocal conclusions about association of the variant with MYH3-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. This variant leads to a translational efficiency of 54% relative to that of the wild-type (Cameron-Christie_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=3, VUS n=1, Benign n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 08, 2023 | The MYH3 c.-9+1G>A variant results in a substitution at a consensus splice donor site that has been shown to result in abnormal splicing with an increase in transcripts lacking exon 2 (PMID: 29805041). This variant was identified in a compound heterozygous state in at least 9 individuals with spondylocarpotarsal synostosis, multiple pterygium syndrome (MPS), and vertebral fusions, arthrogryposis and multiple pterygia (PMID: 29805041; 34440395; 35169139). The highest frequency of this allele in the Genome Aggregation Database is 0.010640 in the European (Finnish) population, however, this variant is not found in the homozygous state but is flagged as low confidence (version 2.1.1). Functional studies conducted in human cell lines demonstrated that transcripts containing the c.-9+1G>A variant lacking exon 2 display a reduced translational efficiency of 54% compared to wild-type (PMID: 29805041). Based on the available evidence, the c.-9+1G>A variant is classified as likely pathogenic for MYH3-related disorders. - |
Contractures, pterygia, and variable skeletal fusions syndrome 1B Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 27, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | This variant affects the canonical donor splice site at the untranslated boundary between exon 2 and intron 2, leading to reduced translational efficiency (Zhao et a., 2022). - |
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 | - - |
Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:1
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NG_011537.1(NM_002470.3):c.-9+1G>A in the MYH3 gene has an allele frequency of 0.011 in European(Finnish) subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in multiple individuals with autosomal recessive Spondylocarpotarsal Synostosis Syndrome, compound heterozygous with c.4647+1G>A, c.141T>G, deletion of intron 12 and exon 25 (PMID: 29805041).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at