16-15756347-A-G

Position:

chr16-15756347-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002474.3(MYH11):c.1743T>C(p.Ala581=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,613,510 control chromosomes in the GnomAD database, including 157,746 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. A581A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.49 ( 19863 hom., cov: 32)

Exomes 𝑓: 0.43 ( 137883 hom. )

Consequence

MYH11
NM_002474.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.675

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 16-15756347-A-G is Benign according to our data. Variant chr16-15756347-A-G is described in ClinVar as [Benign]. Clinvar id is 138327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15756347-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.675 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH11	NM_002474.3 linkuse as main transcript	c.1743T>C	p.Ala581=	synonymous_variant	14/41	ENST00000300036.6
MYH11	NM_001040113.2 linkuse as main transcript	c.1764T>C	p.Ala588=	synonymous_variant	15/43	ENST00000452625.7
MYH11	NM_001040114.2 linkuse as main transcript	c.1764T>C	p.Ala588=	synonymous_variant	15/42
MYH11	NM_022844.3 linkuse as main transcript	c.1743T>C	p.Ala581=	synonymous_variant	14/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.1743T>C	p.Ala581=	synonymous_variant	14/41	1	NM_002474.3	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.1764T>C	p.Ala588=	synonymous_variant	15/43	1	NM_001040113.2		P35749-3

Frequencies

GnomAD3 genomes

AF:

0.493

AC:

74927

AN:

151842

Hom.:

19824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.686

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.385

Gnomad EAS

AF:

0.689

Gnomad SAS

AF:

0.422

Gnomad FIN

AF:

0.380

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.452

GnomAD3 exomes

AF:

0.436

AC:

109390

AN:

250808

Hom.:

25341

AF XY:

0.429

AC XY:

58138

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.691

Gnomad AMR exome

AF:

0.352

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.701

Gnomad SAS exome

AF:

0.398

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.400

GnomAD4 exome

AF:

0.429

AC:

626814

AN:

1461550

Hom.:

137883

Cov.:

AF XY:

0.427

AC XY:

310357

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.689

Gnomad4 AMR exome

AF:

0.356

Gnomad4 ASJ exome

AF:

0.391

Gnomad4 EAS exome

AF:

0.687

Gnomad4 SAS exome

AF:

0.396

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.420

Gnomad4 OTH exome

AF:

0.447

GnomAD4 genome

AF:

0.494

AC:

75022

AN:

151960

Hom.:

19863

Cov.:

AF XY:

0.491

AC XY:

36444

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.687

Gnomad4 AMR

AF:

0.403

Gnomad4 ASJ

AF:

0.385

Gnomad4 EAS

AF:

0.688

Gnomad4 SAS

AF:

0.422

Gnomad4 FIN

AF:

0.380

Gnomad4 NFE

AF:

0.415

Gnomad4 OTH

AF:

0.456

Alfa

AF:

0.421

Hom.:

33019

Bravo

AF:

0.503

Asia WGS

AF:

0.553

AC:

1921

AN:

3478

EpiCase

AF:

0.398

EpiControl

AF:

0.393

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ala588Ala in exon 15 of MYH11: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 40.6% (3489/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2272554). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2012	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. -

Aortic aneurysm, familial thoracic 4

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Visceral myopathy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2015

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

-0.83

CADD

Benign

0.10

DANN

Benign

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over