rs376154041
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6
The NM_002474.3(MYH11):c.5176G>A(p.Ala1726Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,565,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.5176G>A | p.Ala1726Thr | missense_variant | 37/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.5197G>A | p.Ala1733Thr | missense_variant | 38/43 | ENST00000452625.7 | |
NDE1 | NM_017668.3 | c.948-5757C>T | intron_variant | ENST00000396354.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.5176G>A | p.Ala1726Thr | missense_variant | 37/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.5197G>A | p.Ala1733Thr | missense_variant | 38/43 | 1 | NM_001040113.2 | ||
NDE1 | ENST00000396354.6 | c.948-5757C>T | intron_variant | 1 | NM_017668.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 5AN: 178624Hom.: 0 AF XY: 0.0000103 AC XY: 1AN XY: 96666
GnomAD4 exome AF: 0.0000219 AC: 31AN: 1412844Hom.: 0 Cov.: 31 AF XY: 0.0000214 AC XY: 15AN XY: 700240
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2021 | 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. - |
Congenital aneurysm of ascending aorta Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Aug 01, 2016 | Found in patient having exome sequencing for an unrelated indication. No known history of thoracic aortic aneurysm(s). - |
Aortic aneurysm, familial thoracic 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1733 of the MYH11 protein (p.Ala1733Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 375862). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at