chr17-18143622-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_016239.4(MYO15A):c.5964+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,415,476 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016239.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000287 AC: 5AN: 174324Hom.: 0 AF XY: 0.0000214 AC XY: 2AN XY: 93280
GnomAD4 exome AF: 0.00000283 AC: 4AN: 1415476Hom.: 0 Cov.: 38 AF XY: 0.00000286 AC XY: 2AN XY: 699816
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PM3_Strong+PP1_Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 15, 2024 | Variant summary: MYO15A c.5964+3G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a 5' donor site. Two predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.9e-05 in 174324 control chromosomes. c.5964+3G>A has been reported in the literature as compound heterozygous genotype in multiple individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 3 (Gao_2013, Liang_2021, Sun_2019, Zhang_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24206587, 34265623, 30896630, 30953472). ClinVar contains an entry for this variant (Variation ID: 1202140). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnosis Center for Deafness | - | - - |
not provided Pathogenic:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2018 | This variant is associated with the following publications: (PMID: 30896630, 30953472, 27375115, 24206587) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 23, 2023 | This variant is also known as IVS25+3G>A. For these reasons, this variant has been classified as Pathogenic. 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 create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 1202140). This variant has been observed in individual(s) with deafness (PMID: 24206587, 30896630, 30953472, 34265623, 34416374, 34974475, 35346193). 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. This variant is present in population databases (rs530975087, gnomAD 0.04%). This sequence change falls in intron 26 of the MYO15A gene. It does not directly change the encoded amino acid sequence of the MYO15A protein. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at