rs746615097

Positions:

• chr16-15732652-C-A
• chr16-15732652-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002474.3(MYH11):​c.3563G>T​(p.Arg1188Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ENSG00000263335 (HGNC:):

ACMG classification

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
MYH11	NM_002474.3	c.3563G>T	p.Arg1188Leu	missense_variant	27/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3584G>T	p.Arg1195Leu	missense_variant	28/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3584G>T	p.Arg1195Leu	missense_variant	28/42		NP_001035203.1
MYH11	NM_022844.3	c.3563G>T	p.Arg1188Leu	missense_variant	27/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3563G>T	p.Arg1188Leu	missense_variant	27/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3584G>T	p.Arg1195Leu	missense_variant	28/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2014

p.Arg1188Leu (CGG>CTG): c.3563 G>T in exon 27 of the MYH11 gene (NM_002474.2)A variant of unknown significance has been identified in the MYH11 gene. The R1188L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1188L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1188L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, no missense mutations in nearby residues have been reported in association with familial TAAD. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;.;.;D
Eigen	Benign	0.083
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.24	.;.;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Uncertain	0.48
Sift	Benign	0.058	T;T;.;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.94	.;.;.;P
Vest4		0.67
MutPred		0.39		.;.;Loss of MoRF binding (P = 0.0388);Loss of MoRF binding (P = 0.0388);
MVP		0.89
MPC		0.63
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.47
gMVP		0.37

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: rs746615097; hg19: chr16-15826509;