rs113577450

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_002474.3(MYH11):c.546C>T(p.Ala182Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MYH11
NM_002474.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -1.67

Publications

0 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 Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
aortic aneurysm, familial thoracic 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
megacystis-microcolon-intestinal hypoperistalsis syndrome 2
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
megacystis-microcolon-intestinal hypoperistalsis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
visceral myopathy 2
Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

MYH11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 16-15786717-G-A is Benign according to our data. Variant chr16-15786717-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263526.

BP7

Synonymous conserved (PhyloP=-1.67 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000108 (158/1461782) while in subpopulation MID AF = 0.000173 (1/5766). AF 95% confidence interval is 0.000106. There are 0 homozygotes in GnomAdExome4. There are 85 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3 link	c.546C>T	p.Ala182Ala	synonymous_variant	Exon 5 of 41	ENST00000300036.6	NP_002465.1	P35749-1A0A024QZJ4
MYH11	NM_001040113.2 link	c.546C>T	p.Ala182Ala	synonymous_variant	Exon 5 of 43	ENST00000452625.7	NP_001035202.1	P35749-3
MYH11	NM_001040114.2 link	c.546C>T	p.Ala182Ala	synonymous_variant	Exon 5 of 42		NP_001035203.1	P35749-2
MYH11	NM_022844.3 link	c.546C>T	p.Ala182Ala	synonymous_variant	Exon 5 of 42		NP_074035.1	P35749-4A0A024QZJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 link	c.546C>T	p.Ala182Ala	synonymous_variant	Exon 5 of 41	1	NM_002474.3	ENSP00000300036.5		P35749-1
MYH11	ENST00000452625.7 link	c.546C>T	p.Ala182Ala	synonymous_variant	Exon 5 of 43	1	NM_001040113.2	ENSP00000407821.2		P35749-3

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251116

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1461782

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000124

AC:

138

AN:

1111984

Other (OTH)

AF:

0.000182

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

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:

152176

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41534

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.000102

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Oct 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

MYH11-related disorder

Benign:1

Apr 29, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Jan 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.85

(source)

DANN

Benign

0.76

PhyloP100

-1.7

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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