NM_002474.3:c.2961C>G

Variant names:

• chr16-15740087-G-C
• rs137988790
• NM_002474.3:c.2961C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002474.3(MYH11):​c.2961C>G​(p.Ile987Met) 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. 15/21 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.457

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09843987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2961C>G	p.Ile987Met	missense_variant	Exon 23 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2982C>G	p.Ile994Met	missense_variant	Exon 24 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2982C>G	p.Ile994Met	missense_variant	Exon 24 of 42		NP_001035203.1
MYH11	NM_022844.3	c.2961C>G	p.Ile987Met	missense_variant	Exon 23 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2961C>G	p.Ile987Met	missense_variant	Exon 23 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2982C>G	p.Ile994Met	missense_variant	Exon 24 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

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 Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with methionine at codon 994 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 1/251486 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. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with methionine at codon 994 of the MYH11 protein (p.Ile994Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs137988790, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	0.094
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.34	.;.;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.64	.;.;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.58	N;N;.;N
REVEL	Benign	0.26
Sift	Benign	0.069	T;T;.;T
Sift4G	Benign	0.80	T;T;T;T
Polyphen		0.0040	.;.;.;B
Vest4		0.24
MutPred		0.49		.;.;Loss of stability (P = 0.0825);Loss of stability (P = 0.0825);
MVP		0.59
MPC		0.18
ClinPred		0.062	T
GERP RS		1.0
Varity_R		0.069
gMVP		0.33

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: rs137988790; hg19: chr16-15833944;