chr22-36289096-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_002473.6(MYH9):c.4546G>A(p.Val1516Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1516L) has been classified as Pathogenic.
Frequency
Consequence
NM_002473.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.4546G>A | p.Val1516Met | missense_variant | 32/41 | ENST00000216181.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.4546G>A | p.Val1516Met | missense_variant | 32/41 | 1 | NM_002473.6 | P1 | |
MYH9 | ENST00000685801.1 | c.4609G>A | p.Val1537Met | missense_variant | 33/42 | ||||
MYH9 | ENST00000691109.1 | n.4841G>A | non_coding_transcript_exon_variant | 26/35 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461820Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727210
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 18, 2022 | Variant summary: MYH9 c.4546G>A (p.Val1516Met) results in a conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251328 control chromosomes (gnomAD). c.4546G>A has been reported in the literature in a family where 3 family members were affected with a milder form of the disease, i.e. macrothrombocytopenia and granulocyte inclusions without nephropathy, hearing loss or cataracts (Pecci_2010, Pecci_2014, Verver_2016). Two different missense variants affecting the same amino acid residue (c.4546G>C (p.V1516L) and c.4546G>T (p.V1516L)) have been reported in affected individuals (PMIDs: 24643058, 16818291). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.