rs12931799

Positions:

chr16-15747916-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002474.3(MYH11):c.2208C>T(p.Ile736=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,613,904 control chromosomes in the GnomAD database, including 2,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 603 hom., cov: 31)

Exomes 𝑓: 0.042 ( 1901 hom. )

Consequence

MYH11
NM_002474.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.387

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 16-15747916-G-A is Benign according to our data. Variant chr16-15747916-G-A is described in ClinVar as [Benign]. Clinvar id is 36616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15747916-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.387 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH11	NM_002474.3 linkuse as main transcript	c.2208C>T	p.Ile736=	synonymous_variant	18/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2 linkuse as main transcript	c.2229C>T	p.Ile743=	synonymous_variant	19/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2 linkuse as main transcript	c.2229C>T	p.Ile743=	synonymous_variant	19/42		NP_001035203.1
MYH11	NM_022844.3 linkuse as main transcript	c.2208C>T	p.Ile736=	synonymous_variant	18/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.2208C>T	p.Ile736=	synonymous_variant	18/41	1	NM_002474.3	ENSP00000300036	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.2229C>T	p.Ile743=	synonymous_variant	19/43	1	NM_001040113.2	ENSP00000407821		P35749-3

Frequencies

GnomAD3 genomes

AF:

0.0727

AC:

11039

AN:

151914

Hom.:

595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.0954

Gnomad AMR

AF:

0.0524

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.0996

Gnomad FIN

AF:

0.0367

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0355

Gnomad OTH

AF:

0.0662

GnomAD3 exomes

AF:

0.0529

AC:

13315

AN:

251468

Hom.:

588

AF XY:

0.0538

AC XY:

7317

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.0295

Gnomad ASJ exome

AF:

0.0282

Gnomad EAS exome

AF:

0.109

Gnomad SAS exome

AF:

0.0939

Gnomad FIN exome

AF:

0.0362

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0430

GnomAD4 exome

AF:

0.0419

AC:

61240

AN:

1461872

Hom.:

1901

Cov.:

AF XY:

0.0431

AC XY:

31314

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.147

Gnomad4 AMR exome

AF:

0.0304

Gnomad4 ASJ exome

AF:

0.0264

Gnomad4 EAS exome

AF:

0.107

Gnomad4 SAS exome

AF:

0.0889

Gnomad4 FIN exome

AF:

0.0365

Gnomad4 NFE exome

AF:

0.0333

Gnomad4 OTH exome

AF:

0.0512

GnomAD4 genome

AF:

0.0729

AC:

11076

AN:

152032

Hom.:

603

Cov.:

AF XY:

0.0737

AC XY:

5476

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.147

Gnomad4 AMR

AF:

0.0523

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.107

Gnomad4 SAS

AF:

0.101

Gnomad4 FIN

AF:

0.0367

Gnomad4 NFE

AF:

0.0355

Gnomad4 OTH

AF:

0.0722

Alfa

AF:

0.0412

Hom.:

238

Bravo

AF:

0.0763

Asia WGS

AF:

0.0980

AC:

339

AN:

3478

EpiCase

AF:

0.0348

EpiControl

AF:

0.0342

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ile743Ile in exon 19 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 14.5% (636/4394) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12931799). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
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	- -

Aortic aneurysm, familial thoracic 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial aortopathy

Benign:1

Benign, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2014

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

-0.46

CADD

Benign

6.1

DANN

Benign

0.78

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

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