rs751041617
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2
The NM_002473.6(MYH9):c.170A>T(p.Glu57Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 1 hom. )
Consequence
MYH9
NM_002473.6 missense
NM_002473.6 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 8.02
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 Likely_benign. Variant got -4 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). GenCC has associacion of 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.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000103 (15/1461894) while in subpopulation SAS AF= 0.000162 (14/86258). AF 95% confidence interval is 0.0000979. There are 1 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.170A>T | p.Glu57Val | missense_variant | 2/41 | ENST00000216181.11 | NP_002464.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.170A>T | p.Glu57Val | missense_variant | 2/41 | 1 | NM_002473.6 | ENSP00000216181.6 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251466Hom.: 1 AF XY: 0.0000515 AC XY: 7AN XY: 135916
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461894Hom.: 1 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727248
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
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 | Jan 20, 2018 | The p.Glu57Val variant MYH9 has not been previously reported in individuals with hearing loss, but has been identified in 8/30782 South Asian chromosomes, inclu ding a homozygous individual, by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs751041617). Although this variant has been s een in the general population, its frequency is not high enough to rule out a pa thogenic role. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Glu57Val variant is uncertain. ACMG/AMP criteria applied: PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;D
Polyphen
P;P;.
Vest4
MutPred
Loss of disorder (P = 0.0312);Loss of disorder (P = 0.0312);Loss of disorder (P = 0.0312);
MVP
MPC
ClinPred
D
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