rs1314103972
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_002474.3(MYH11):c.2342A>T(p.Glu781Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,934 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Consequence
MYH11
NM_002474.3 missense
NM_002474.3 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.824
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.2342A>T | p.Glu781Val | missense_variant | 19/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.2363A>T | p.Glu788Val | missense_variant | 20/43 | ENST00000452625.7 | |
MYH11 | NM_001040114.2 | c.2363A>T | p.Glu788Val | missense_variant | 20/42 | ||
MYH11 | NM_022844.3 | c.2342A>T | p.Glu781Val | missense_variant | 19/42 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.2342A>T | p.Glu781Val | missense_variant | 19/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.2363A>T | p.Glu788Val | missense_variant | 20/43 | 1 | NM_001040113.2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151934Hom.: 0 Cov.: 31
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GnomAD4 exome Cov.: 33
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151934Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74166
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 465716). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 788 of the MYH11 protein (p.Glu788Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;.;L;L
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;D
Sift4G
Benign
T;T;T;T
Polyphen
1.0
.;.;.;D
Vest4
MutPred
0.48
.;.;Loss of disorder (P = 0.0148);Loss of disorder (P = 0.0148);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at