16-15823313-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_002474.3(MYH11):ā€‹c.444C>Gā€‹(p.His148Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.682
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 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH11NM_002474.3 linkuse as main transcriptc.444C>G p.His148Gln missense_variant 3/41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkuse as main transcriptc.444C>G p.His148Gln missense_variant 3/43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkuse as main transcriptc.444C>G p.His148Gln missense_variant 3/42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkuse as main transcriptc.444C>G p.His148Gln missense_variant 3/42 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkuse as main transcriptc.444C>G p.His148Gln missense_variant 3/411 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkuse as main transcriptc.444C>G p.His148Gln missense_variant 3/431 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251484
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461892
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2022The p.H148Q variant (also known as c.444C>G), located in coding exon 2 of the MYH11 gene, results from a C to G substitution at nucleotide position 444. The histidine at codon 148 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Uncertain
0.020
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.80
.;.;.;D
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.52
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.83
T;T;T;T
M_CAP
Uncertain
0.22
D
MetaRNN
Uncertain
0.49
T;T;T;T
MetaSVM
Benign
-0.29
T
MutationAssessor
Benign
0.74
N;N;N;N
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.8
D;D;.;D
REVEL
Uncertain
0.64
Sift
Benign
0.034
D;D;.;D
Sift4G
Benign
0.22
T;T;T;T
Polyphen
0.49
.;.;.;P
Vest4
0.58
MutPred
0.35
Gain of methylation at K145 (P = 0.0952);Gain of methylation at K145 (P = 0.0952);Gain of methylation at K145 (P = 0.0952);Gain of methylation at K145 (P = 0.0952);
MVP
0.95
MPC
1.8
ClinPred
0.50
D
GERP RS
2.5
Varity_R
0.55
gMVP
0.58

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: rs569925780; hg19: chr16-15917170; API