rs4781689

chr16-15771615-G-Achr16-15771615-G-Cchr16-15771615-G-T

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.987C>T(p.Thr329=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0962 in 1,613,660 control chromosomes in the GnomAD database, including 8,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (700 hom., cov: 29)
  • Exomes 𝑓: 0.098 (7962 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0670

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=-0.65).
• BP6: Variant 16-15771615-G-A is Benign according to our data. Variant chr16-15771615-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15771615-G-A is described in Lovd as [Benign]. Variant chr16-15771615-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.067 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.987C>T	p.Thr329=	synonymous_variant	9/41	ENST00000300036.6
MYH11	NM_001040113.2	c.1008C>T	p.Thr336=	synonymous_variant	10/43	ENST00000452625.7
MYH11	NM_001040114.2	c.1008C>T	p.Thr336=	synonymous_variant	10/42
MYH11	NM_022844.3	c.987C>T	p.Thr329=	synonymous_variant	9/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.987C>T	p.Thr329=	synonymous_variant	9/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.1008C>T	p.Thr336=	synonymous_variant	10/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12201 AN: 151706 Hom.: 696 Cov.: 29

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0702

Gnomad EAS AF: 0.00387

Gnomad SAS AF: 0.0985

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0681

GnomAD3 exomes AF: 0.107 AC: 26978 AN: 251460 Hom.: 1999 AF XY: 0.105 AC XY: 14298 AN XY: 135900

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.0769

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.0996

Gnomad OTH exome AF: 0.0979

GnomAD4 exome AF: 0.0978 AC: 142950 AN: 1461836 Hom.: 7962 Cov.: 33 AF XY: 0.0977 AC XY: 71016 AN XY: 727218

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.0732

Gnomad4 EAS exome AF: 0.00640

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.0975

Gnomad4 OTH exome AF: 0.0833

GnomAD4 genome AF: 0.0805 AC: 12216 AN: 151824 Hom.: 700 Cov.: 29 AF XY: 0.0857 AC XY: 6359 AN XY: 74184

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0702

Gnomad4 EAS AF: 0.00388

Gnomad4 SAS AF: 0.0995

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0670

Alfa AF: 0.0927 Hom.: 1168

Bravo AF: 0.0734

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0885

EpiControl AF: 0.0887

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
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 specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Thr336Thr in exon 10 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 9.9% (855/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4781689). -
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:2

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	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 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	-0.65
Cadd	Benign	3.3
Dann	Benign	0.45

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: rs4781689; hg19: chr16-15865472;