rs1050111

chr16-15823340-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.417C>T(p.Val139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,614,076 control chromosomes in the GnomAD database, including 9,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (865 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8929 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.874

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=-0.67).
• BP6: Variant 16-15823340-G-A is Benign according to our data. Variant chr16-15823340-G-A is described in ClinVar as [Benign]. Clinvar id is 138366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15823340-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.874 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.417C>T	p.Val139=	synonymous_variant	3/41	ENST00000300036.6
MYH11	NM_001040113.2	c.417C>T	p.Val139=	synonymous_variant	3/43	ENST00000452625.7
MYH11	NM_001040114.2	c.417C>T	p.Val139=	synonymous_variant	3/42
MYH11	NM_022844.3	c.417C>T	p.Val139=	synonymous_variant	3/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.417C>T	p.Val139=	synonymous_variant	3/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.417C>T	p.Val139=	synonymous_variant	3/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15662 AN: 152090 Hom.: 864 Cov.: 33

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0830

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.0994 AC: 24992 AN: 251486 Hom.: 1347 AF XY: 0.0993 AC XY: 13500 AN XY: 135922

Gnomad AFR exome AF: 0.0869

Gnomad AMR exome AF: 0.0691

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.0946

Gnomad SAS exome AF: 0.0599

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.108 AC: 157475 AN: 1461868 Hom.: 8929 Cov.: 34 AF XY: 0.107 AC XY: 77872 AN XY: 727244

Gnomad4 AFR exome AF: 0.0846

Gnomad4 AMR exome AF: 0.0690

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.0651

Gnomad4 SAS exome AF: 0.0625

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.103 AC: 15675 AN: 152208 Hom.: 865 Cov.: 33 AF XY: 0.102 AC XY: 7594 AN XY: 74398

Gnomad4 AFR AF: 0.0848

Gnomad4 AMR AF: 0.0944

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.0834

Gnomad4 SAS AF: 0.0549

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.110

Alfa AF: 0.113 Hom.: 592

Bravo AF: 0.101

Asia WGS AF: 0.0590 AC: 205 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:10

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	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	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 23, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Val139Val in exon 3 of MYH11: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 11.8% (1012/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1050111). -

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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	7.2
Dann	Benign	0.86

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: rs1050111; hg19: chr16-15917197; COSMIC: COSV55551037;