chr19-50293327-T-C
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001145809.2(MYH14):c.5345+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,444,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
MYH14
NM_001145809.2 splice_donor_region, intron
NM_001145809.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.8954
2
Clinical Significance
Conservation
PhyloP100: 2.07
Genes affected
MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BS2
High AC in GnomAdExome4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH14 | NM_001145809.2 | c.5345+6T>C | splice_donor_region_variant, intron_variant | ENST00000642316.2 | |||
MYH14 | NM_001077186.2 | c.5246+6T>C | splice_donor_region_variant, intron_variant | ||||
MYH14 | NM_024729.4 | c.5222+6T>C | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH14 | ENST00000642316.2 | c.5345+6T>C | splice_donor_region_variant, intron_variant | NM_001145809.2 |
Frequencies
GnomAD3 genomes Cov.: 32
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32
GnomAD3 exomes AF: 0.0000138 AC: 3AN: 217922Hom.: 0 AF XY: 0.0000170 AC XY: 2AN XY: 117574
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GnomAD4 exome AF: 0.00000554 AC: 8AN: 1444018Hom.: 0 Cov.: 31 AF XY: 0.00000837 AC XY: 6AN XY: 716616
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 30, 2015 | The c.5345+6T>C variant in MYH14 has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant. Computational tools do not suggest an impact t o splicing. However, this information is not predictive enough to rule out patho genicity. In summary, the clinical significance of the c.5345+6T>C variant is un certain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2021 | Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has not been reported in the literature in individuals with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 228879). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 36 of the MYH14 gene. It does not directly change the encoded amino acid sequence of the MYH14 protein. It affects a nucleotide within the consensus splice site of the intron. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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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