16-15747911-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002474.3(MYH11):​c.2213A>C​(p.Lys738Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K738R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

MYH11
NM_002474.3 missense

Scores

13
4
2

Clinical Significance

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

Conservation

PhyloP100: 8.00

Publications

0 publications found
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]
MYH11 Gene-Disease associations (from GenCC):
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • aortic aneurysm, familial thoracic 4
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • megacystis-microcolon-intestinal hypoperistalsis syndrome 2
    Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • megacystis-microcolon-intestinal hypoperistalsis syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • visceral myopathy 2
    Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH11NM_002474.3 linkc.2213A>C p.Lys738Thr missense_variant Exon 18 of 41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.2234A>C p.Lys745Thr missense_variant Exon 19 of 43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkc.2234A>C p.Lys745Thr missense_variant Exon 19 of 42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkc.2213A>C p.Lys738Thr missense_variant Exon 18 of 42 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkc.2213A>C p.Lys738Thr missense_variant Exon 18 of 41 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.2234A>C p.Lys745Thr missense_variant Exon 19 of 43 1 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
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:2
Mar 06, 2024
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces lysine with threonine at codon 745 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 27, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces lysine with threonine at codon 745 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
.;.;.;D
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.84
D;D;D;D
MetaSVM
Uncertain
0.67
D
MutationAssessor
Benign
1.7
.;.;L;L
PhyloP100
8.0
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-5.7
D;D;.;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0020
D;D;.;D
Sift4G
Uncertain
0.028
D;T;T;T
Polyphen
0.98
.;.;.;D
Vest4
0.71
MutPred
0.47
.;.;Loss of methylation at K738 (P = 0.0067);Loss of methylation at K738 (P = 0.0067);
MVP
0.96
MPC
2.0
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.79
gMVP
0.84
Mutation Taster
=33/67
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1555560379; hg19: chr16-15841768; API