rs762239398
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_002473.6(MYH9):c.1890C>T(p.Thr630=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,830 control chromosomes in the GnomAD database, including 2 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000063 ( 2 hom. )
Consequence
MYH9
NM_002473.6 synonymous
NM_002473.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.928
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 -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.62).
BP6
?
Variant 22-36306561-G-A is Benign according to our data. Variant chr22-36306561-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227603.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
BP7
?
Synonymous conserved (PhyloP=-0.928 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000629 (92/1461608) while in subpopulation MID AF= 0.00121 (7/5762). AF 95% confidence interval is 0.00057. There are 2 homozygotes in gnomad4_exome. There are 48 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAdExome4 at 92 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.1890C>T | p.Thr630= | synonymous_variant | 16/41 | ENST00000216181.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.1890C>T | p.Thr630= | synonymous_variant | 16/41 | 1 | NM_002473.6 | P1 | |
MYH9 | ENST00000685801.1 | c.1953C>T | p.Thr651= | synonymous_variant | 17/42 | ||||
MYH9 | ENST00000687922.1 | n.226C>T | non_coding_transcript_exon_variant | 2/3 | |||||
MYH9 | ENST00000691109.1 | n.2185C>T | non_coding_transcript_exon_variant | 10/35 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000440 AC: 11AN: 249854Hom.: 1 AF XY: 0.0000517 AC XY: 7AN XY: 135418
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GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461608Hom.: 2 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 727092
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | MYH9: BP4, BP7 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | - - |
Autosomal dominant nonsyndromic hearing loss 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2015 | p.Thr630Thr in exon 16 of MYH9: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. The variant has been identified in 2/65194 E uropean chromosomes and 2/16314 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). - |
MYH9-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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