rs397516284
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000260.4(MYO7A):c.132+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000763 in 1,442,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000260.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.132+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.132+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000260.4 | ||||
MYO7A | ENST00000409619.6 | c.99+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | |||||
MYO7A | ENST00000458637.6 | c.132+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | P1 | ||||
MYO7A | ENST00000660626.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000763 AC: 11AN: 1442306Hom.: 0 Cov.: 30 AF XY: 0.00000838 AC XY: 6AN XY: 715658
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 02, 2010 | The 132+5G>A variant has not been reported in the literature but was identified by our laboratory in a patient with Usher syndrome and a second MYO7A variant. T he 132+5G>A variant is located in the 5' splice region and affects the +5 positi on which is the most conserved position after the +1 and +2 positions. In summar y, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change falls in intron 3 of the MYO7A gene. It does not directly change the encoded amino acid sequence of the MYO7A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with deafness and/or Usher syndrome (PMID: 27208204; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43140). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Retinal dystrophy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at