chr16-15740090-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002474.3(MYH11):​c.2958G>C​(p.Glu986Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. E986K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH11
NM_002474.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.370
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.041172415).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH11NM_002474.3 linkc.2958G>C p.Glu986Asp missense_variant Exon 23 of 41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.2979G>C p.Glu993Asp missense_variant Exon 24 of 43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkc.2979G>C p.Glu993Asp missense_variant Exon 24 of 42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkc.2958G>C p.Glu986Asp missense_variant Exon 23 of 42 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkc.2958G>C p.Glu986Asp missense_variant Exon 23 of 41 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.2979G>C p.Glu993Asp missense_variant Exon 24 of 43 1 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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
Nov 01, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid with aspartic acid at codon 993 of the MYH11 protein (p.Glu993Asp). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH11-related disease. 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 aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.092
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
3.9
DANN
Benign
0.75
DEOGEN2
Benign
0.30
.;.;.;T
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.86
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.74
T;T;T;T
M_CAP
Uncertain
0.096
D
MetaRNN
Benign
0.041
T;T;T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
-0.34
.;.;N;N
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
1.8
N;N;.;N
REVEL
Benign
0.21
Sift
Benign
1.0
T;T;.;T
Sift4G
Benign
0.67
T;T;T;T
Polyphen
0.0
.;.;.;B
Vest4
0.10
MutPred
0.28
.;.;Loss of ubiquitination at K981 (P = 0.1576);Loss of ubiquitination at K981 (P = 0.1576);
MVP
0.40
MPC
0.16
ClinPred
0.056
T
GERP RS
-5.8
Varity_R
0.052
gMVP
0.16

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: rs774274573; hg19: chr16-15833947; API