rs35035518
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1
The NM_002474.3(MYH11):c.2648C>T(p.Ser883Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S883S) has been classified as Likely benign.
Frequency
Consequence
NM_002474.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.2648C>T | p.Ser883Leu | missense_variant | 21/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.2669C>T | p.Ser890Leu | missense_variant | 22/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.2669C>T | p.Ser890Leu | missense_variant | 22/42 | ||
MYH11 | NM_022844.3 | c.2648C>T | p.Ser883Leu | missense_variant | 21/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.2648C>T | p.Ser883Leu | missense_variant | 21/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.2669C>T | p.Ser890Leu | missense_variant | 22/43 | 1 | NM_001040113.2 | ||
ENST00000577048.1 | n.523G>A | non_coding_transcript_exon_variant | 2/2 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.000296 AC: 45AN: 152134Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000390 AC: 98AN: 251478Hom.: 1 AF XY: 0.000375 AC XY: 51AN XY: 135914
GnomAD4 exome AF: 0.000272 AC: 398AN: 1461880Hom.: 0 Cov.: 30 AF XY: 0.000285 AC XY: 207AN XY: 727238
GnomAD4 genome ? AF: 0.000296 AC: 45AN: 152252Hom.: 1 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74440
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 11, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 07, 2018 | - - |
Aortic aneurysm, familial thoracic 4 Uncertain:1Benign: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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | MYH11: BP4 - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2020 | Variant summary: MYH11 c.2669C>T (p.Ser890Leu) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 251478 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 312 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2669C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (2x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. - |
MYH11-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 26, 2024 | 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