16-15778831-G-A

Position:

• chr16-15778831-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PP2 PP3 BP4_Moderate BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:17 O:1
• Conservation: PhyloP100: 3.18

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]

ACMG classification

Verdict is Benign. Variant got -9 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: 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: {Likely_benign=12, not_provided=1, Benign=1, Uncertain_significance=3}. 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/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.739C>T	p.Arg247Cys	missense_variant	7/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.760C>T	p.Arg254Cys	missense_variant	8/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.760C>T	p.Arg254Cys	missense_variant	8/42		NP_001035203.1
MYH11	NM_022844.3	c.739C>T	p.Arg247Cys	missense_variant	7/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.739C>T	p.Arg247Cys	missense_variant	7/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.760C>T	p.Arg254Cys	missense_variant	8/43	1	NM_001040113.2	ENSP00000407821

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152030 Hom.: 1 Cov.: 31

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.: 1 AF XY: 0.00169 AC XY: 229 AN XY: 135902

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.: 11 Cov.: 32 AF XY: 0.00250 AC XY: 1817 AN XY: 727234

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.: 1 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74368

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.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00194 AC: 236

EpiCase AF: 0.00267

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:17 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 22, 2015	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

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	Mar 01, 2024	MYH11: PP3, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

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. -
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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 25, 2023	- -

not specified Benign:2

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 -
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. -

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	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.4	.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
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	T
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

Other links and lift over

dbSNP: rs150759461; hg19: chr16-15872688; COSMIC: COSV55569227;