rs12907

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_002474.3(MYH11):c.3967C>T(p.Leu1323Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0291 in 1,613,774 control chromosomes in the GnomAD database, including 2,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1323L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.085 ( 1387 hom., cov: 32)

Exomes 𝑓: 0.023 ( 1430 hom. )

Consequence

MYH11
NM_002474.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 5.90

Publications

9 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 16-15724796-G-A is Benign according to our data. Variant chr16-15724796-G-A is described in ClinVar as Benign. ClinVar VariationId is 138338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.3967C>T	p.Leu1323Leu	synonymous_variant	Exon 30 of 41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 31 of 43	ENST00000452625.7	NP_001035202.1	P35749-3
NDE1	NM_017668.3 link	c.*545G>A		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.3967C>T	p.Leu1323Leu	synonymous_variant	Exon 30 of 41	1	NM_002474.3	ENSP00000300036.5	P35749-1
MYH11	ENST00000452625.7 link	c.3988C>T	p.Leu1330Leu	synonymous_variant	Exon 31 of 43	1	NM_001040113.2	ENSP00000407821.2	P35749-3
NDE1	ENST00000396354.6 link	c.*545G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_017668.3	ENSP00000379642.1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.0845

AC:

12856

AN:

152060

Hom.:

1387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0370

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.0346

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.0330

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0593

GnomAD2 exomes

AF:

0.0358

AC:

8994

AN:

251106

AF XY:

0.0320

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.0200

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.0278

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0287

GnomAD4 exome

AF:

0.0233

AC:

34107

AN:

1461596

Hom.:

1430

Cov.:

AF XY:

0.0229

AC XY:

16657

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.260

AC:

8712

AN:

33480

American (AMR)

AF:

0.0227

AC:

1013

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

559

AN:

26136

East Asian (EAS)

AF:

0.0345

AC:

1368

AN:

39700

South Asian (SAS)

AF:

0.0270

AC:

2332

AN:

86258

European-Finnish (FIN)

AF:

0.0284

AC:

1511

AN:

53138

Middle Eastern (MID)

AF:

0.0385

AC:

222

AN:

5768

European-Non Finnish (NFE)

AF:

0.0147

AC:

16311

AN:

1112002

Other (OTH)

AF:

0.0344

AC:

2079

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2267

4533

6800

9066

11333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

770

1540

2310

3080

3850

<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:

0.0847

AC:

12883

AN:

152178

Hom.:

1387

Cov.:

AF XY:

0.0839

AC XY:

6242

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.252

AC:

10473

AN:

41486

American (AMR)

AF:

0.0368

AC:

563

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3470

East Asian (EAS)

AF:

0.0346

AC:

179

AN:

5168

South Asian (SAS)

AF:

0.0195

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0330

AC:

350

AN:

10608

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0149

AC:

1015

AN:

68018

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

502

1004

1506

2008

2510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0345

Hom.:

524

Bravo

AF:

0.0921

Asia WGS

AF:

0.0400

AC:

139

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Sep 19, 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

Leu1330Leu in exon 31 of MYH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 24.3% (1068/4394) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12907). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Jul 07, 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 -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 4

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 25, 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

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=27/73

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