rs144813247

Positions:

• chr16-15719673-C-A
• chr16-15719673-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_002474.3(MYH11):​c.4994G>T​(p.Arg1665Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.61

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]

MYH11 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4994G>T	p.Arg1665Leu	missense_variant	35/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5015G>T	p.Arg1672Leu	missense_variant	36/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-4518C>A		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4994G>T	p.Arg1665Leu	missense_variant	35/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5015G>T	p.Arg1672Leu	missense_variant	36/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-4518C>A		intron_variant		1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251482 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135918

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: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.0000665

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 21, 2024	The p.R1665L variant (also known as c.4994G>T), located in coding exon 34 of the MYH11 gene, results from a G to T substitution at nucleotide position 4994. The arginine at codon 1665 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 19, 2022	This missense variant replaces arginine with leucine at codon 1672 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282884 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2024	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 29, 2016	Genetic testing looked for variants in 15 genes associated with aneurysms and dissections: ACTA2, COL3A1, FBN1, FBN2, MAT2A, MYH11, MYLK, MYH11, PRKG1, SKI, SLC2A10, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2. Analysis also included deletion/duplication studies using comparative genomic hybridization for all of the genes mentioned above. Results reported on September 29, 2016 show that no disease-causing variants were found. However, a variant of unknown significance was found: See report below. p.Arg1665Leu (c.4994G>T) in the MYH11 gene (NM_002474.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data and presence in the general population we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated cases of FTAAD (not including this patient's family) that is listed in Clinvar with no additional data clinical data. The Arg at codon 1665 is not well conserved across species, and neither are neighboring amino acids. Pufferfish (His), Zebrafish (His), and fruit fly (Lys) all have different amino acids at this position. Other variants have not been reported in association with disease at this codon or in nearby codons. Missense variation has been reported as pathogenic and likely pathogenic in other individuals in clinvar. This variant is not in a known protein domain. There is significant variation at codon 1665 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >126,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. 10 individuals have the same p.Arg1665Leu variant our patient has, 9 individuals have p.Arg1665His, and 12 individuals have p.Arg1665Cys. In total, 29 individuals have variation at this position for a total frequency of 1 in 4344 individuals in the general population which is likely too common for this variant to play a strong role in causing aneurysms and dissections. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1672 of the MYH11 protein (p.Arg1672Leu). This variant is present in population databases (rs144813247, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 201081). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	.;.;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.9	D;D;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.027	D;D;.;D
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.99	.;.;.;D
Vest4		0.71
MVP		0.64
MPC		0.62
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.55

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: rs144813247; hg19: chr16-15813530; COSMIC: COSV99037577; COSMIC: COSV99037577;