rs144813247

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1665C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.61

Variant links:

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 links:

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]

NDE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
MYH11	NM_002474.3 linkuse as main transcript	c.4994G>T	p.Arg1665Leu	missense_variant	35/41	ENST00000300036.6
MYH11	NM_001040113.2 linkuse as main transcript	c.5015G>T	p.Arg1672Leu	missense_variant	36/43	ENST00000452625.7
NDE1	NM_017668.3 linkuse as main transcript	c.948-4518C>A		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.4994G>T	p.Arg1665Leu	missense_variant	35/41	1	NM_002474.3	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.5015G>T	p.Arg1672Leu	missense_variant	36/43	1	NM_001040113.2		P35749-3
NDE1	ENST00000396354.6 linkuse as main transcript	c.948-4518C>A		intron_variant		1	NM_017668.3	P1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

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:

AN:

251482

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135918

show subpopulations

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:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727240

show subpopulations

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:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

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.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 24, 2021	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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2023	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; This variant is associated with the following publications: (PMID: 26582918) -

Aortic aneurysm, familial thoracic 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;.;.;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.9

.;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over