rs12931799

chr16-15747916-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.387

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]

ACMG classification

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	UniProt
MYH11	NM_002474.3	c.2208C>T	p.Ile736=	synonymous_variant	18/41	ENST00000300036.6
MYH11	NM_001040113.2	c.2229C>T	p.Ile743=	synonymous_variant	19/43	ENST00000452625.7
MYH11	NM_001040114.2	c.2229C>T	p.Ile743=	synonymous_variant	19/42
MYH11	NM_022844.3	c.2208C>T	p.Ile736=	synonymous_variant	18/42

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0727 AC: 11039 AN: 151914 Hom.: 595 Cov.: 31

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

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.: 34 AF XY: 0.0431 AC XY: 31314 AN XY: 727238

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.: 31 AF XY: 0.0737 AC XY: 5476 AN XY: 74304

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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). -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

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	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
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	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	Invitae	Feb 01, 2024	- -

Familial aortopathy Benign:1

Benign, criteria provided, single submitter

curation

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

Aug 18, 2011

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 11, 2023

- -

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

Other links and lift over

dbSNP: rs12931799; hg19: chr16-15841773; COSMIC: COSV55555025; COSMIC: COSV55555025;