chr16-15756347-A-G

Position:

• chr16-15756347-A-G

Variant summary

Our verdict is Benign. Variant got -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:14
• Conservation: PhyloP100: -0.675

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 (HGNC:):

ACMG classification

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	Protein	UniProt
MYH11	NM_002474.3	c.1743T>C	p.Ala581Ala	synonymous_variant	14/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.1764T>C	p.Ala588Ala	synonymous_variant	15/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.1764T>C	p.Ala588Ala	synonymous_variant	15/42		NP_001035203.1
MYH11	NM_022844.3	c.1743T>C	p.Ala581Ala	synonymous_variant	14/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.1743T>C	p.Ala581Ala	synonymous_variant	14/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.1764T>C	p.Ala588Ala	synonymous_variant	15/43	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

GnomAD3 exomes AF: 0.436 AC: 109390 AN: 250808 Hom.: 25341 AF XY: 0.429 AC XY: 58138 AN XY: 135604

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

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.: 32 AF XY: 0.491 AC XY: 36444 AN XY: 74278

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:4

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	Color Diagnostics, LLC DBA Color Health	Mar 16, 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	Oct 03, 2024	- -

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
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	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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Other links and lift over

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