rs759372006
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_004999.4(MYO6):āc.217C>Gā(p.Leu73Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000489 in 1,430,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000049 ( 0 hom. )
Consequence
MYO6
NM_004999.4 missense
NM_004999.4 missense
Scores
1
11
5
Clinical Significance
Conservation
PhyloP100: 3.68
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 Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO6 | NM_004999.4 | c.217C>G | p.Leu73Val | missense_variant | 4/35 | ENST00000369977.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO6 | ENST00000369977.8 | c.217C>G | p.Leu73Val | missense_variant | 4/35 | 1 | NM_004999.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250788Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135594
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000489 AC: 7AN: 1430084Hom.: 0 Cov.: 27 AF XY: 0.00000841 AC XY: 6AN XY: 713434
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GnomAD4 genome ? Cov.: 32
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ExAC
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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 | Apr 20, 2017 | The p.Leu73Val variant in MYO6 has not been previously reported in individuals w ith hearing loss, but has been identified in 5/17242 East Asian chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759372006). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analyses do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Leu7 3Val variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2022 | ClinVar contains an entry for this variant (Variation ID: 505686). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO6 protein function. This variant has not been reported in the literature in individuals affected with MYO6-related conditions. This variant is present in population databases (rs759372006, gnomAD 0.03%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 73 of the MYO6 protein (p.Leu73Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;.;D;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;.;D;.
Sift4G
Benign
T;T;T;T;T;T
Polyphen
1.0, 0.92
.;D;P;D;.;.
Vest4
MutPred
Gain of methylation at K78 (P = 0.0748);Gain of methylation at K78 (P = 0.0748);Gain of methylation at K78 (P = 0.0748);Gain of methylation at K78 (P = 0.0748);Gain of methylation at K78 (P = 0.0748);Gain of methylation at K78 (P = 0.0748);
MVP
MPC
0.26
ClinPred
D
GERP RS
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at