16-15756358-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_002474.3(MYH11):āc.1732A>Gā(p.Ile578Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00065 in 1,614,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002474.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.1732A>G | p.Ile578Val | missense_variant | 14/41 | ENST00000300036.6 | NP_002465.1 | |
MYH11 | NM_001040113.2 | c.1753A>G | p.Ile585Val | missense_variant | 15/43 | ENST00000452625.7 | NP_001035202.1 | |
MYH11 | NM_001040114.2 | c.1753A>G | p.Ile585Val | missense_variant | 15/42 | NP_001035203.1 | ||
MYH11 | NM_022844.3 | c.1732A>G | p.Ile578Val | missense_variant | 14/42 | NP_074035.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.1732A>G | p.Ile578Val | missense_variant | 14/41 | 1 | NM_002474.3 | ENSP00000300036.5 | ||
MYH11 | ENST00000452625.7 | c.1753A>G | p.Ile585Val | missense_variant | 15/43 | 1 | NM_001040113.2 | ENSP00000407821.2 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000617 AC: 155AN: 251388Hom.: 1 AF XY: 0.000692 AC XY: 94AN XY: 135892
GnomAD4 exome AF: 0.000666 AC: 974AN: 1461878Hom.: 2 Cov.: 35 AF XY: 0.000642 AC XY: 467AN XY: 727240
GnomAD4 genome AF: 0.000493 AC: 75AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74436
ClinVar
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | MYH11: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 24, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2016 | Variant summary: This c.1753A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ile to Val. 3/3 in-silico tools predict this variant to be benign (SNPs&GO and Mutation Taster not captured here due to low reliability index and p-value, respectively). The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 97/121158 (1/1249), which exceeds the predicted maximum expected allele frequency for a pathogenic MYH11 variant of 1/769230. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a reputable clinical laboratory cites the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 14, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 14, 2018 | - - |
Aortic aneurysm, familial thoracic 4 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
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. - |
MYH11-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2021 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at