16-15778831-G-A

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

15
2
2

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]

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
MYH11NM_002474.3 linkc.739C>T p.Arg247Cys missense_variant Exon 7 of 41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.760C>T p.Arg254Cys missense_variant Exon 8 of 43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkc.760C>T p.Arg254Cys missense_variant Exon 8 of 42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkc.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
MYH11ENST00000300036.6 linkc.739C>T p.Arg247Cys missense_variant Exon 7 of 41 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.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.:
1
Cov.:
31
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.:
1
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.:
11
Cov.:
32
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.:
1
Cov.:
31
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.:
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:4Benign:18Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1Benign:6
Nov 30, 2018
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 19, 2016
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 23, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 04, 2014
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 22, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:4
Jan 25, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 16, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 19, 2020
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 02, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MYH11: PP3, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 09, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2
Oct 22, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 31, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Apr 11, 2014
Blueprint Genetics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Connective tissue disorder Uncertain:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1
Mar 30, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 05, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Congenital aneurysm of ascending aorta;C1851504:Aortic aneurysm, familial thoracic 4 Other:1
-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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
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

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

Other links and lift over

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