rs763151112

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_002474.3(MYH11):​c.598T>G​(p.Ser200Ala) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

MYH11
NM_002474.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.44
Variant links:
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 2 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.3932946).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH11NM_002474.3 linkuse as main transcriptc.598T>G p.Ser200Ala missense_variant 5/41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkuse as main transcriptc.598T>G p.Ser200Ala missense_variant 5/43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkuse as main transcriptc.598T>G p.Ser200Ala missense_variant 5/42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkuse as main transcriptc.598T>G p.Ser200Ala missense_variant 5/42 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkuse as main transcriptc.598T>G p.Ser200Ala missense_variant 5/411 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkuse as main transcriptc.598T>G p.Ser200Ala missense_variant 5/431 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 06, 2024- -
Aortic aneurysm, familial thoracic 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 31, 2017In 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 missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MYH11-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with alanine at codon 200 of the MYH11 protein (p.Ser200Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
.;.;.;T
Eigen
Benign
0.019
Eigen_PC
Benign
0.18
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.39
T;T;T;T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Benign
0.20
N;N;N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.59
N;N;.;N
REVEL
Uncertain
0.60
Sift
Benign
0.34
T;T;.;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.69
.;.;.;P
Vest4
0.48
MutPred
0.39
Loss of catalytic residue at S200 (P = 0.0568);Loss of catalytic residue at S200 (P = 0.0568);Loss of catalytic residue at S200 (P = 0.0568);Loss of catalytic residue at S200 (P = 0.0568);
MVP
0.85
MPC
1.5
ClinPred
0.95
D
GERP RS
5.3
Varity_R
0.21
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763151112; hg19: chr16-15880522; API