Genetic Variant NM_002474.3:c.5676G>C (chr16-15715019-C-G) – ACMG Classification: Benign (-20 pts)

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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
microcephaly with lissencephaly and/or hydranencephaly
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH11	NM_002474.3	MANE Select	c.5676G>C	p.Glu1892Asp	missense	Exon 40 of 41	NP_002465.1	P35749-1
MYH11	NM_001040113.2	MANE Plus Clinical	c.5697G>C	p.Glu1899Asp	missense	Exon 41 of 43	NP_001035202.1	P35749-3
NDE1	NM_017668.3	MANE Select	c.948-9172C>G		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5676G>C	p.Glu1892Asp	missense	Exon 40 of 41	ENSP00000300036.5	P35749-1
MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5697G>C	p.Glu1899Asp	missense	Exon 41 of 43	ENSP00000407821.2	P35749-3
MYH11	ENST00000396324.7	TSL:1	c.5697G>C	p.Glu1899Asp	missense	Exon 41 of 42	ENSP00000379616.3	P35749-2

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aortic aneurysm, familial thoracic 4 (6)

not specified (5)

not provided (3)

Familial thoracic aortic aneurysm and aortic dissection (2)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.037

MutationAssessor

Pathogenic

3.2

PhyloP100

2.6

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.035

Polyphen

0.88

Vest4

0.66

MutPred

0.39

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

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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

Computational scores

Splicing

Publications

Other links and lift over