rs587781047

chr16-15748148-G-AchrNT_187607.1-1406158-G-A

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.2079C>T(p.Phe693=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,613,896 control chromosomes in the GnomAD database, including 1,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (892 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (758 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.462

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-15748148-G-A is Benign according to our data. Variant chr16-15748148-G-A is described in ClinVar as [Benign]. Clinvar id is 138329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15748148-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.462 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.2079C>T	p.Phe693=	synonymous_variant	17/41	ENST00000300036.6
MYH11	NM_001040113.2	c.2100C>T	p.Phe700=	synonymous_variant	18/43	ENST00000452625.7
MYH11	NM_001040114.2	c.2100C>T	p.Phe700=	synonymous_variant	18/42
MYH11	NM_022844.3	c.2079C>T	p.Phe693=	synonymous_variant	17/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.2079C>T	p.Phe693=	synonymous_variant	17/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.2100C>T	p.Phe700=	synonymous_variant	18/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 8869 AN: 152124 Hom.: 887 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0165 AC: 4133 AN: 250988 Hom.: 371 AF XY: 0.0124 AC XY: 1680 AN XY: 135750

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000840

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00668 AC: 9771 AN: 1461654 Hom.: 758 Cov.: 34 AF XY: 0.00587 AC XY: 4268 AN XY: 727136

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.000903

Gnomad4 NFE exome AF: 0.000857

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0584 AC: 8894 AN: 152242 Hom.: 892 Cov.: 32 AF XY: 0.0569 AC XY: 4233 AN XY: 74442

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0263 Hom.: 193

Bravo AF: 0.0662

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:10

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Phe700Phe in exon 18 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 18.6% (818/4394) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34287137). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2013	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 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 07, 2022	- -

Aortic aneurysm, familial thoracic 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 21, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2015

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.78
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34287137; hg19: chr16-15842005; COSMIC: COSV55546844; COSMIC: COSV55546844;