16-15823339-C-T

Position:

• chr16-15823339-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_002474.3(MYH11):​c.418G>A​(p.Asp140Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.86

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• 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=0.24382427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.418G>A	p.Asp140Asn	missense_variant	3/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.418G>A	p.Asp140Asn	missense_variant	3/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.418G>A	p.Asp140Asn	missense_variant	3/42		NP_001035203.1
MYH11	NM_022844.3	c.418G>A	p.Asp140Asn	missense_variant	3/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.418G>A	p.Asp140Asn	missense_variant	3/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.418G>A	p.Asp140Asn	missense_variant	3/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

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: 0.0000423

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 02, 2023	This missense variant replaces aspartic acid with asparagine at codon 140 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with osteogenesis imperfecta (PMID: 30684648). The individual's sister, niece and father were also diagnosed with osteogenesis imperfecta, and father was also affected with aortic dissection. This variant has been identified in 3/282890 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2024	The p.D140N variant (also known as c.418G>A), located in coding exon 2 of the MYH11 gene, results from a G to A substitution at nucleotide position 418. The aspartic acid at codon 140 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in a subject with features of osteogenesis imperfecta and a family history of thoracic aortic aneurysm and dissection, who also carried a frameshift alteration in COL1A1 (Balasubramanian M et al. Bone, 2019 Apr;121:191-195). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces aspartic acid with asparagine at codon 140 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with osteogenesis imperfecta (PMID: 30684648). The individual's sister, niece and father were also diagnosed with osteogenesis imperfecta, and father was also affected with aortic dissection. This variant has been identified in 3/282890 chromosomes 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2017	A variant of uncertain significance has been identified in the MYH11 gene. The D140N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D140N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position where amino acids with similar properties to aspartic acid are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2021

This sequence change replaces aspartic acid with asparagine at codon 140 of the MYH11 protein (p.Asp140Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of MYH11-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 426591). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;.;.;D
Eigen	Benign	-0.092
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.20	N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N;.;N
REVEL	Benign	0.25
Sift	Benign	0.087	T;T;.;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0040	.;.;.;B
Vest4		0.27
MutPred		0.34		Gain of MoRF binding (P = 0.0579);Gain of MoRF binding (P = 0.0579);Gain of MoRF binding (P = 0.0579);Gain of MoRF binding (P = 0.0579);
MVP		0.74
MPC		1.5
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.10
gMVP		0.52

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

Other links and lift over

dbSNP: rs1085307699; hg19: chr16-15917196; COSMIC: COSV55558416;