NM_002474.3:c.3842A>T

Variant names:

• chr16-15726864-T-A
• rs1060500730
• NM_002474.3:c.3842A>T

Variant summary

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

The NM_002474.3(MYH11):​c.3842A>T​(p.Lys1281Ile) 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: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.459

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3842A>T	p.Lys1281Ile	missense_variant	Exon 28 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3863A>T	p.Lys1288Ile	missense_variant	Exon 29 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3863A>T	p.Lys1288Ile	missense_variant	Exon 29 of 42		NP_001035203.1
MYH11	NM_022844.3	c.3842A>T	p.Lys1281Ile	missense_variant	Exon 28 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3842A>T	p.Lys1281Ile	missense_variant	Exon 28 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3863A>T	p.Lys1288Ile	missense_variant	Exon 29 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1

Oct 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH11-related disease. This sequence change replaces lysine with isoleucine at codon 1288 of the MYH11 protein (p.Lys1288Ile). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;.;.;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	.;.;M;M
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.4	D;D;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Benign	0.076	T;T;T;T
Polyphen		0.93	.;.;.;P
Vest4		0.49
MutPred		0.62		.;.;Loss of ubiquitination at K1281 (P = 0.0022);Loss of ubiquitination at K1281 (P = 0.0022);
MVP		0.73
MPC		0.47
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.69
gMVP		0.32

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: rs1060500730; hg19: chr16-15820721;