rs727503284
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>T(p.Val1516Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1516M) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.4546G>T | p.Val1516Leu | missense_variant | 32/41 | ENST00000216181.11 | NP_002464.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.4546G>T | p.Val1516Leu | missense_variant | 32/41 | 1 | NM_002473.6 | ENSP00000216181 | P1 | |
MYH9 | ENST00000685801.1 | c.4609G>T | p.Val1537Leu | missense_variant | 33/42 | ENSP00000510688 | ||||
MYH9 | ENST00000691109.1 | n.4841G>T | non_coding_transcript_exon_variant | 26/35 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 19, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 10, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with MYH9-related disorders (PMID: 16818291, 24643058). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164432). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 1516 of the MYH9 protein (p.Val1516Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 09, 2017 | The p.Val1516Leu variant has been identified in two Chinese individuals with MYH 9 related disease (MYH9-RD), and segregated in 6 affected relatives across the t wo families (Ma 2006, LMM data). This variant has not been reported in large pop ulation studies. The same missense variant resulting from a different DNA change (c.4546G>C, p.Val1516Leu) has also been reported in an individual with MYH9-RD and segregated in 8 affected family members (Zhang 2014). Furthermore, another missense variant at the same amino acid position (p.Val1516Met) has also been id entified in one family with features of MYH9-RD (Pecci 2010, Pecci 2013). In sum mary, this variant meets criteria to be classified as pathogenic for autosomal d ominant MYH9-RD based on the evidence described above. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at