rs727504743
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS1
The NM_004999.4(MYO6):c.2907_2909del(p.Glu970del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000103 in 1,607,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000095 ( 0 hom. )
Consequence
MYO6
NM_004999.4 inframe_deletion
NM_004999.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.79
Genes affected
MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_004999.4. Strenght limited to Supporting due to length of the change: 1aa.
BP6
?
Variant 6-75891256-CAAG-C is Benign according to our data. Variant chr6-75891256-CAAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179255.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000171 (26/152026) while in subpopulation AMR AF= 0.00111 (17/15260). AF 95% confidence interval is 0.000709. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO6 | NM_004999.4 | c.2907_2909del | p.Glu970del | inframe_deletion | 27/35 | ENST00000369977.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO6 | ENST00000369977.8 | c.2907_2909del | p.Glu970del | inframe_deletion | 27/35 | 1 | NM_004999.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 151908Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000202 AC: 50AN: 247662Hom.: 0 AF XY: 0.000217 AC XY: 29AN XY: 133880
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GnomAD4 exome AF: 0.0000955 AC: 139AN: 1455644Hom.: 0 AF XY: 0.0000953 AC XY: 69AN XY: 724198
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GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74304
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2020 | The c.2907_2909delAGA variant in the MYO6 gene has been reported previously in association with nonsyndromic SNHL with limited evidence for pathogenicity (Sommen et al., 2016). The variant is observed in 1/836 (0.1196%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The c.2907_2909delAGA variant results in an in-frame deletion of one amino acid. In summary, based on the currently available information, it is unclear whether this is a pathogenic variant or a rare benign variant. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 13, 2018 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Mar 19, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 29, 2021 | The p.Glu970del variant in MYO6 is likely benign because it has been identified in 0.08% (29/35102) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). The variant has been reported in 1 European individual with sensorineural hearing loss (Sommen 2016 PMID:27068579), and our lab has seen this variant in 1 individual with hearing loss who carried additional pathogenic variants sufficient to explain their clinical presentation. This variant has also been reported in ClinVar (Variation ID 179255). This variant is a deletion of 1 amino acids at position 970 and is not predicted to alter the protein reading-frame. ACMG/AMP Criteria applied:PM4_Supporting, BS1, BP5. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at