16-15778831-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_002474.3(MYH11):c.739C>T(p.Arg247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,024 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0026 ( 11 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:18O:1

Conservation

PhyloP100: 3.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.15796763).

BP6

Variant 16-15778831-G-A is Benign according to our data. Variant chr16-15778831-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161317.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=13, not_provided=1}. Variant chr16-15778831-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (250/152150) while in subpopulation NFE AF= 0.00288 (196/67998). AF 95% confidence interval is 0.00255. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.739C>T	p.Arg247Cys	missense_variant	Exon 7 of 41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.760C>T	p.Arg254Cys	missense_variant	Exon 8 of 43	ENST00000452625.7	NP_001035202.1	P35749-3
MYH11	NM_001040114.2 link	c.760C>T	p.Arg254Cys	missense_variant	Exon 8 of 42		NP_001035203.1	P35749-2
MYH11	NM_022844.3 link	c.739C>T	p.Arg247Cys	missense_variant	Exon 7 of 42		NP_074035.1	P35749-4A0A024QZJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 link	c.739C>T	p.Arg247Cys	missense_variant	Exon 7 of 41	1	NM_002474.3	ENSP00000300036.5		P35749-1
MYH11	ENST00000452625.7 link	c.760C>T	p.Arg254Cys	missense_variant	Exon 8 of 43	1	NM_001040113.2	ENSP00000407821.2		P35749-3

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

251

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00290

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00174

AC:

438

AN:

251466

Hom.:

AF XY:

0.00169

AC XY:

229

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00313

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00262

AC:

3833

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

1817

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00307

Gnomad4 NFE exome

AF:

0.00318

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152150

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.00288

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00194

AC:

236

EpiCase

AF:

0.00267

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:18Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4

Uncertain:1Benign:6

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 30, 2018	MYH11 NM_002474.2 exon 7 p.Arg247Cys (c.739C>T): This variant has been reported in the literature (also referred to as p.Arg254Cys) in at least one individual with abdominal aortic aneurysm, segregating with disease in one affected family member (Van de Luijtgaarden 2015 PMID:26017485). This variant is present in 0.3% (393/129162) of European alleles in the Genome Aggregation Database, including 2 homozygotes (http://gnomad.broadinstitute.org/variant/16-15872688-G-A). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:161317). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Kuang 2012 PMID: 22511748; Bellini 2015 PMID: 25433566). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 23, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 22, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 19, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	This variant is associated with the following publications: (PMID: 22968129, 16444274, 25407000, 24337657, 10854329, 22511748, 25433566, 26893369, 27879251, 27153395, 29494672, 17956658, 17666408, 14722581, 10199307, 7923625, 26792327, 25424711, 24676022, 27418595, 26017485, 25637381, 26332594, 27535533, 29961567, 32220188, 32068640) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MYH11: PP3, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2019	Variant summary: MYH11 c.760C>T (p.Arg254Cys, also known as c.739C>T/p.Arg247Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 282840 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2400 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.760C>T, has been reported in the literature in at least one family with 2 affected individuals (Van de Luijtgaarden_2015), and in patients with aortic disease and no family history (Kuang_2012). These reports however do not provide unequivocal conclusions about association of the variant with Aortopathy. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the p.Arg247Cys substitution decreases the ATPase activity (actin-activated), and the rate of actin filament sliding, and in a knock-in mouse model the mutant aorta displayed a decreased contractile response, but there was no overall vascular phenotype under normal conditions in either homozygous or heterozygous mice (Kuang_2012, Huang_2018). However, the homozygous mutant knock-in mice were more vulnerable to alterations in hemodynamic loading (Bellini_2015), or developed aortic dilation when crossed with the ACTA2 +/- mice, indicating that two variants not known to cause disease may lead to aortic enlargement in combination (Kwartler_2018). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign 7x, VUS 2x). Based on the evidence outlined above, the variant is unlikely to cause familial thoracic aortic disease, but more evidence is required to determine if it might represent a low penetrance risk variant, therefore it was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.3% European; ClinVar: 2 VUS, 1 LB -

Loeys-Dietz syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Apr 11, 2014

- -

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

MYH11 NM_002474.2 exon 7 p.Arg247Cys (c.739C>T): This variant has been reported in the literature (also referred to as p.Arg254Cys) in at least one individual with abdominal aortic aneurysm, segregating with disease in one affected family member (Van de Luijtgaarden 2015 PMID:26017485). This variant is present in 0.3% (393/129162) of European alleles in the Genome Aggregation Database, including 2 homozygotes (http://gnomad.broadinstitute.org/variant/16-15872688-G-A). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:161317). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Kuang 2012 PMID: 22511748; Bellini 2015 PMID: 25433566). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

MYH11-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Altered myosin contractile function

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Congenital aneurysm of ascending aorta;C1851504:Aortic aneurysm, familial thoracic 4

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 03/28/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

.;.;.;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.4

.;.;M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.0

D;D;.;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.89

MVP

0.92

MPC

1.9

ClinPred

0.14

GERP RS

5.1

Varity_R

0.76

gMVP

0.84

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