rs76368635
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_002473.6(MYH9):c.4198C>T(p.Arg1400Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,124 control chromosomes in the GnomAD database, including 7 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 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0019 ( 7 hom. )
Consequence
MYH9
NM_002473.6 missense
NM_002473.6 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 3.26
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 -9 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH9. . Gene score misZ: 3.473 (greater than the threshold 3.09). Trascript score misZ: 6.1231 (greater than threshold 3.09). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 84 curated benign missense variants. GenCC has associacion of the gene with May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.
BP4
Computational evidence support a benign effect (MetaRNN=0.33464932).
BP6
Variant 22-36292132-G-A is Benign according to our data. Variant chr22-36292132-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44562.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=8, Benign=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (178/152314) while in subpopulation NFE AF= 0.00196 (133/68028). AF 95% confidence interval is 0.00168. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 178 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.4198C>T | p.Arg1400Trp | missense_variant | 31/41 | ENST00000216181.11 | NP_002464.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.4198C>T | p.Arg1400Trp | missense_variant | 31/41 | 1 | NM_002473.6 | ENSP00000216181.6 | ||
MYH9 | ENST00000685801.1 | c.4261C>T | p.Arg1421Trp | missense_variant | 32/42 | ENSP00000510688.1 | ||||
MYH9 | ENST00000691109.1 | n.4493C>T | non_coding_transcript_exon_variant | 25/35 |
Frequencies
GnomAD3 genomes AF: 0.00117 AC: 178AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000998 AC: 251AN: 251412Hom.: 1 AF XY: 0.000971 AC XY: 132AN XY: 135894
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GnomAD4 exome AF: 0.00193 AC: 2824AN: 1461810Hom.: 7 Cov.: 32 AF XY: 0.00183 AC XY: 1332AN XY: 727206
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GnomAD4 genome AF: 0.00117 AC: 178AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 27, 2023 | BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | MYH9: BS1 - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 05, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2021 | This variant is associated with the following publications: (PMID: 30720677, 11752022, 22123909, 30245029, 22477015, 27577878, 26764160, 24448499, 22995991, 20981092) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 04, 2013 | Arg1400Trp in exon 31 of MYH9: This variant is not expected to have clinical sig nificance because it has been identified in 7/122 (5.7%) control chromosomes (Be rg 2013) and has been seen in 0.2% (19/6980) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7 6368635). It has been reported in the literature in individuals with macrothromb ocytopenia with or without renal impairment (Arrondel 2001, Jang 2012, Sanborn 2 011), however lack of clear segregation with disease and limited control informa tion in these studies do not support a strong association between this variant and macrothrombocytopenia. In summary, the frequency of this variant in the gene ral population supports a benign role. - |
MYH9-related disorder Benign:2
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 23, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Meniere disease Uncertain:1
Uncertain significance, no assertion criteria provided | research | Center for Computational Biology & Bioinformatics, University of California, San Diego | Jun 03, 2024 | - - |
Autosomal dominant nonsyndromic hearing loss 17 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
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