rs749181134

chr16-15721604-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_002474.3(MYH11):c.4396A>C(p.Lys1466Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.4396A>C	p.Lys1466Gln	missense_variant	32/41	ENST00000300036.6
MYH11	NM_001040113.2	c.4417A>C	p.Lys1473Gln	missense_variant	33/43	ENST00000452625.7
NDE1	NM_017668.3	c.948-2587T>G		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.4396A>C	p.Lys1466Gln	missense_variant	32/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.4417A>C	p.Lys1473Gln	missense_variant	33/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.948-2587T>G		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital aneurysm of ascending aorta Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing for an unrelated indication. No known history of thoracic aortic aneurysm(s). -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2016

The p.K1466Q variant (also known as c.4396A>C), located in coding exon 31 of the MYH11 gene, results from an A to C substitution at nucleotide position 4396. The lysine at codon 1466 is replaced by glutamine, an amino acid with similar properties, and is located in the coiled coil domain. Based on data from ExAC (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed April 7, 2016]), the C allele has an overall frequency of <0.01% (1/106209). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 13, 2021

This sequence change replaces lysine with glutamine at codon 1473 of the MYH11 protein (p.Lys1473Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs749181134, ExAC 0.003%). This missense change has been observed in individual(s) with clinical features of MYH11-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 375854). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.15
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Benign	0.69
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.93	N;N;.;N
REVEL	Uncertain	0.44
Sift	Benign	0.49	T;T;.;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.040	.;.;.;B
Vest4		0.65
MutPred		0.36		.;.;Loss of ubiquitination at K1466 (P = 0.002);Loss of ubiquitination at K1466 (P = 0.002);
MVP		0.73
MPC		0.72
ClinPred		0.39	T
GERP RS		4.8
Varity_R		0.27
gMVP		0.36

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: rs749181134; hg19: chr16-15815461;