NM_001040113.2:c.5818C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001040113.2(MYH11):c.5818C>G(p.Pro1940Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,610,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1940R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

MYH11
NM_001040113.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.06

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021141022).

BP6

Variant 16-15708831-G-C is Benign according to our data. Variant chr16-15708831-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374962.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000394 (6/152272) while in subpopulation AMR AF = 0.000262 (4/15282). AF 95% confidence interval is 0.0000888. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040113.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH11	NM_001040113.2	MANE Plus Clinical	c.5818C>G	p.Pro1940Ala	missense	Exon 42 of 43	NP_001035202.1
MYH11	NM_002474.3	MANE Select	c.5787-4708C>G		intron	N/A	NP_002465.1
NDE1	NM_017668.3	MANE Select	c.947+11971G>C		intron	N/A	NP_060138.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5818C>G	p.Pro1940Ala	missense	Exon 42 of 43	ENSP00000407821.2
MYH11	ENST00000576790.7	TSL:1	c.5797C>G	p.Pro1933Ala	missense	Exon 41 of 42	ENSP00000458731.1
MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5787-4708C>G		intron	N/A	ENSP00000300036.5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

240868

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.0000666

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1457864

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

724660

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33440

American (AMR)

AF:

0.000998

AC:

AN:

44084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25960

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000588

AC:

AN:

84986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110560

Other (OTH)

AF:

0.0000166

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41548

American (AMR)

AF:

0.000262

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4

Uncertain:1Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 04, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Apr 16, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 25, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Mar 19, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge; Reported using an alternate transcript of the gene

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.41

M_CAP

Benign

0.036

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.73

PhyloP100

3.1

PROVEAN

Benign

-0.22

REVEL

Benign

0.23

Sift

Benign

0.19

Sift4G

Benign

0.62

Vest4

0.42

MVP

0.42

ClinPred

0.066

GERP RS

4.2

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over