chr16-15740090-C-G

Position:

• chr16-15740090-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.370

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041172415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2958G>C	p.Glu986Asp	missense_variant	23/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2979G>C	p.Glu993Asp	missense_variant	24/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2979G>C	p.Glu993Asp	missense_variant	24/42		NP_001035203.1
MYH11	NM_022844.3	c.2958G>C	p.Glu986Asp	missense_variant	23/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2958G>C	p.Glu986Asp	missense_variant	23/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.2979G>C	p.Glu993Asp	missense_variant	24/43	1	NM_001040113.2	ENSP00000407821

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

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2017

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
MutationTaster	Benign	1.0	N;N;N;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

Other links and lift over

dbSNP: rs774274573; hg19: chr16-15833947;