chr17-18141643-C-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_016239.4(MYO15A):c.5532-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,314 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 3 hom. )
Consequence
MYO15A
NM_016239.4 splice_polypyrimidine_tract, intron
NM_016239.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.0001387
2
Clinical Significance
Conservation
PhyloP100: 0.0160
Genes affected
MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 17-18141643-C-T is Benign according to our data. Variant chr17-18141643-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164529.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.5532-10C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000647165.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.5532-10C>T | splice_polypyrimidine_tract_variant, intron_variant | NM_016239.4 | P1 | ||||
MYO15A | ENST00000412324.1 | n.543-10C>T | splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.000585 AC: 89AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000541 AC: 135AN: 249408Hom.: 0 AF XY: 0.000539 AC XY: 73AN XY: 135358
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GnomAD4 exome AF: 0.00138 AC: 2019AN: 1461044Hom.: 3 Cov.: 31 AF XY: 0.00125 AC XY: 907AN XY: 726896
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GnomAD4 genome AF: 0.000584 AC: 89AN: 152270Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29AN XY: 74454
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 24, 2017 | c.5532-10C>T in intron 22 of MYO15A: This variant is not expected to have clinic al significance because a C>T change at this position does not diverge from the splice consensus sequence and is therefore unlikely to impact splicing. It has b een identified in 0.1% (119/126584) of European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200169924). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at