rs1243566183

Variant names:

• chr16-15745203-T-A
• rs1243566183
• NM_002474.3:c.2446A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-15745203-T-A
• chr16-15745203-T-C
• chr16-15745203-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002474.3(MYH11):​c.2446A>T​(p.Met816Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18846771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2446A>T	p.Met816Leu	missense_variant	Exon 20 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2467A>T	p.Met823Leu	missense_variant	Exon 21 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2467A>T	p.Met823Leu	missense_variant	Exon 21 of 42		NP_001035203.1
MYH11	NM_022844.3	c.2446A>T	p.Met816Leu	missense_variant	Exon 20 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2446A>T	p.Met816Leu	missense_variant	Exon 20 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2467A>T	p.Met823Leu	missense_variant	Exon 21 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 823 of the MYH11 protein (p.Met823Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 465717). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function. 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	0.27
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.26	.;.;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.45	.;.;N;N
PhyloP100		5.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.10	N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.54	T;T;.;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.37
MutPred		0.52		.;.;Loss of stability (P = 0.1204);Loss of stability (P = 0.1204);
MVP		0.39
MPC		0.82
ClinPred		0.66	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.69
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1243566183; hg19: chr16-15839060;