rs113964173

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002474.3(MYH11):c.5676G>C(p.Glu1892Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 1,613,984 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts 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. E1892K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 35 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.62

Publications

17 publications found

Variant links:

COSMIC-nc: COSV100260597

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=0.013423175).

BP6

Variant 16-15715019-C-G is Benign according to our data. Variant chr16-15715019-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.005 (761/152312) while in subpopulation AMR AF = 0.00791 (121/15306). AF 95% confidence interval is 0.00676. There are 4 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.5676G>C	p.Glu1892Asp	missense_variant	Exon 40 of 41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.5697G>C	p.Glu1899Asp	missense_variant	Exon 41 of 43	ENST00000452625.7	NP_001035202.1	P35749-3
NDE1	NM_017668.3 link	c.948-9172C>G		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1	Q9NXR1-2X5DR54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH11	ENST00000300036.6 link	c.5676G>C	p.Glu1892Asp	missense_variant	Exon 40 of 41	1	NM_002474.3	ENSP00000300036.5	P35749-1
MYH11	ENST00000452625.7 link	c.5697G>C	p.Glu1899Asp	missense_variant	Exon 41 of 43	1	NM_001040113.2	ENSP00000407821.2	P35749-3
NDE1	ENST00000396354.6 link	c.948-9172C>G		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

761

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00792

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00907

GnomAD2 exomes

AF:

0.00507

AC:

1273

AN:

251278

AF XY:

0.00536

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00659

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00576

Gnomad NFE exome

AF:

0.00612

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.00569

AC:

8321

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

4148

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33480

American (AMR)

AF:

0.00689

AC:

308

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00539

AC:

141

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86258

European-Finnish (FIN)

AF:

0.00594

AC:

316

AN:

53204

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00607

AC:

6750

AN:

1112008

Other (OTH)

AF:

0.00677

AC:

409

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

538

1076

1615

2153

2691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.00500

AC:

761

AN:

152312

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

362

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41558

American (AMR)

AF:

0.00791

AC:

121

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00610

AC:

415

AN:

68030

Other (OTH)

AF:

0.00898

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00604

Hom.:

Bravo

AF:

0.00533

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.00513

AC:

623

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4

Benign:6

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 31, 2017

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

- -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Dec 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu1899Asp in exon 41 of MYH11: This variant is not expected to have clinical significance because it has been identified in 0.5% (623/121214) of pan ethnic c hromosomes including 3 homozygous individuals by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org/; dbSNP rs113964173). -

Jun 23, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP6 -

not provided

Benign:3

Oct 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH11: BS2; NDE1: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Oct 06, 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: 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. -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;.;.;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.037

MutationAssessor

Pathogenic

3.2

.;.;M;M

PhyloP100

2.6

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.6

D;D;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

D;D;.;D

Sift4G

Uncertain

0.035

D;D;D;D

Polyphen

0.88

.;.;.;P

Vest4

0.66

MutPred

0.39

.;.;Gain of MoRF binding (P = 0.092);Gain of MoRF binding (P = 0.092);

MVP

0.84

MPC

0.68

ClinPred

0.038

GERP RS

1.1

Varity_R

0.68

gMVP

0.33

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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