chr16-15756347-A-G

Variant names:

• chr16-15756347-A-G
• rs2272554
• NM_002474.3:c.1743T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):​c.1743T>C​(p.Ala581Ala) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.675
• Publications: 24 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 138327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.1743T>C	p.Ala581Ala	synonymous_variant	Exon 14 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.1764T>C	p.Ala588Ala	synonymous_variant	Exon 15 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.1764T>C	p.Ala588Ala	synonymous_variant	Exon 15 of 42		NP_001035203.1
MYH11	NM_022844.3	c.1743T>C	p.Ala581Ala	synonymous_variant	Exon 14 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.1743T>C	p.Ala581Ala	synonymous_variant	Exon 14 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.1764T>C	p.Ala588Ala	synonymous_variant	Exon 15 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74927 AN: 151842 Hom.: 19824 Cov.: 32

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

GnomAD2 exomes AF: 0.436 AC: 109390 AN: 250808 AF XY: 0.429

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 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.: 54 AF XY: 0.427 AC XY: 310357 AN XY: 727064

African (AFR) AF: 0.689 AC: 23056 AN: 33472

American (AMR) AF: 0.356 AC: 15887 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 10221 AN: 26132

East Asian (EAS) AF: 0.687 AC: 27264 AN: 39692

South Asian (SAS) AF: 0.396 AC: 34161 AN: 86246

European-Finnish (FIN) AF: 0.387 AC: 20666 AN: 53402

Middle Eastern (MID) AF: 0.314 AC: 1803 AN: 5738

European-Non Finnish (NFE) AF: 0.420 AC: 466762 AN: 1111806

Other (OTH) AF: 0.447 AC: 26994 AN: 60382

GnomAD4 genome AF: 0.494 AC: 75022 AN: 151960 Hom.: 19863 Cov.: 32 AF XY: 0.491 AC XY: 36444 AN XY: 74278

African (AFR) AF: 0.687 AC: 28450 AN: 41438

American (AMR) AF: 0.403 AC: 6152 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1336 AN: 3470

East Asian (EAS) AF: 0.688 AC: 3543 AN: 5146

South Asian (SAS) AF: 0.422 AC: 2033 AN: 4818

European-Finnish (FIN) AF: 0.380 AC: 4013 AN: 10560

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28212 AN: 67952

Other (OTH) AF: 0.456 AC: 962 AN: 2110

Alfa AF: 0.436 Hom.: 71857

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:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Feb 19, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4 Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Visceral myopathy 2 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Feb 03, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.68
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2272554; hg19: chr16-15850204; COSMIC: COSV55543893;