16-15756433-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002474.3(MYH11):​c.1657C>G​(p.Leu553Val) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH11
NM_002474.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28593868).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH11NM_002474.3 linkc.1657C>G p.Leu553Val missense_variant Exon 14 of 41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.1678C>G p.Leu560Val missense_variant Exon 15 of 43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkc.1678C>G p.Leu560Val missense_variant Exon 15 of 42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkc.1657C>G p.Leu553Val missense_variant Exon 14 of 42 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkc.1657C>G p.Leu553Val missense_variant Exon 14 of 41 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.1678C>G p.Leu560Val missense_variant Exon 15 of 43 1 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Feb 04, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1657C>G (p.L553V) alteration is located in exon 14 (coding exon 13) of the MYH11 gene. This alteration results from a C to G substitution at nucleotide position 1657, causing the leucine (L) at amino acid position 553 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Uncertain
0.074
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Uncertain
0.60
.;.;.;D
Eigen
Benign
-0.16
Eigen_PC
Benign
0.0024
FATHMM_MKL
Benign
0.36
N
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.29
T;T;T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
1.6
.;.;L;L
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.91
N;N;.;N
REVEL
Uncertain
0.31
Sift
Benign
0.30
T;T;.;T
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.0010
.;.;.;B
Vest4
0.29
MutPred
0.77
.;.;Gain of ubiquitination at K552 (P = 0.1235);Gain of ubiquitination at K552 (P = 0.1235);
MVP
0.80
MPC
0.79
ClinPred
0.51
D
GERP RS
4.4
Varity_R
0.14
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs1555562404; hg19: chr16-15850290; API