NM_002474.3:c.3866T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002474.3(MYH11):c.3866T>C(p.Val1289Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 1,613,508 control chromosomes in the GnomAD database, including 3,024 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1289L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.040 ( 164 hom., cov: 32)

Exomes 𝑓: 0.058 ( 2860 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 7.34

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

lissencephaly 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
hydranencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microlissencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
NDE1-related microhydranencephaly
Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

NDE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034478605).

BP6

Variant 16-15724985-A-G is Benign according to our data. Variant chr16-15724985-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.3866T>C	p.Val1289Ala	missense_variant	Exon 29 of 41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.3887T>C	p.Val1296Ala	missense_variant	Exon 30 of 43	ENST00000452625.7	NP_001035202.1	P35749-3
NDE1	NM_017668.3 link	c.*734A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000396354.6	NP_060138.1	Q9NXR1-2X5DR54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH11	ENST00000300036.6 link	c.3866T>C	p.Val1289Ala	missense_variant	Exon 29 of 41	1	NM_002474.3	ENSP00000300036.5	P35749-1
MYH11	ENST00000452625.7 link	c.3887T>C	p.Val1296Ala	missense_variant	Exon 30 of 43	1	NM_001040113.2	ENSP00000407821.2	P35749-3
NDE1	ENST00000396354.6 link	c.*734A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_017668.3	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.0402

AC:

6113

AN:

152054

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0347

Gnomad ASJ

AF:

0.0571

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0230

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0665

Gnomad OTH

AF:

0.0403

GnomAD2 exomes

AF:

0.0396

AC:

9944

AN:

251062

AF XY:

0.0411

show subpopulations

Gnomad AFR exome

AF:

0.00986

Gnomad AMR exome

AF:

0.0229

Gnomad ASJ exome

AF:

0.0639

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.0611

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0581

AC:

84925

AN:

1461336

Hom.:

2860

Cov.:

AF XY:

0.0575

AC XY:

41802

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.00923

AC:

309

AN:

33478

American (AMR)

AF:

0.0245

AC:

1096

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0626

AC:

1636

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0277

AC:

2386

AN:

86240

European-Finnish (FIN)

AF:

0.0183

AC:

974

AN:

53240

Middle Eastern (MID)

AF:

0.0513

AC:

296

AN:

5766

European-Non Finnish (NFE)

AF:

0.0672

AC:

74737

AN:

1111684

Other (OTH)

AF:

0.0577

AC:

3485

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

4273

8546

12818

17091

21364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2718

5436

8154

10872

13590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0402

AC:

6112

AN:

152172

Hom.:

164

Cov.:

AF XY:

0.0364

AC XY:

2710

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0114

AC:

475

AN:

41536

American (AMR)

AF:

0.0347

AC:

530

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

198

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0235

AC:

113

AN:

4816

European-Finnish (FIN)

AF:

0.0138

AC:

146

AN:

10602

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0665

AC:

4521

AN:

67980

Other (OTH)

AF:

0.0399

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

302

604

907

1209

1511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0567

Hom.:

583

Bravo

AF:

0.0407

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0605

AC:

233

ESP6500AA

AF:

0.0137

AC:

ESP6500EA

AF:

0.0651

AC:

560

ExAC

AF:

0.0388

AC:

4711

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0638

EpiControl

AF:

0.0587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val1296Ala in exon 30 of MYH11: This variant is not expected to have clinical si gnificance because it has been identified in 6.5% (560/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16967510). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 4

Benign:4

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Jun 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Lissencephaly 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lissencephaly, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

.;.;.;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D;D

MetaRNN

Benign

0.0034

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.28

.;.;N;N

PhyloP100

7.3

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

N;N;.;N

REVEL

Benign

0.20

Sift

Benign

0.16

T;T;.;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.069

.;.;.;B

Vest4

0.30

MPC

0.28

ClinPred

0.028

GERP RS

5.2

Varity_R

0.094

gMVP

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over