rs201021615
Positions:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2
The NM_002473.6(MYH9):c.5188C>T(p.Arg1730Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000072 in 1,611,792 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1730H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000069 ( 1 hom. )
Consequence
MYH9
NM_002473.6 missense
NM_002473.6 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 6.52
Genes affected
MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MYH9
BP6
?
Variant 22-36285744-G-A is Benign according to our data. Variant chr22-36285744-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164417.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000985 (15/152214) while in subpopulation EAS AF= 0.00135 (7/5198). AF 95% confidence interval is 0.000632. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.5188C>T | p.Arg1730Cys | missense_variant | 37/41 | ENST00000216181.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.5188C>T | p.Arg1730Cys | missense_variant | 37/41 | 1 | NM_002473.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000146 AC: 36AN: 246134Hom.: 0 AF XY: 0.000158 AC XY: 21AN XY: 133116
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GnomAD4 exome AF: 0.0000692 AC: 101AN: 1459578Hom.: 1 Cov.: 32 AF XY: 0.0000647 AC XY: 47AN XY: 725994
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GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74376
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27393652) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 10, 2014 | The Arg1730Cys variant in MYH9 has not been previously reported in individuals w ith hearing loss, but it was identified in 0.02% (1/4022) of African American ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs201021615). Computational prediction tools and conservation analysis suggest that the Arg1730Cys variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of the Arg1730Cys variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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