rs587781046

Positions:

• chr16-15748166-G-A
• chrNT_187607.1-1406177-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.2061C>T​(p.Ser687Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,613,574 control chromosomes in the GnomAD database, including 4,133 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (335 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3798 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.89

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=-0.95).
• BP6: Variant 16-15748166-G-A is Benign according to our data. Variant chr16-15748166-G-A is described in ClinVar as [Benign]. Clinvar id is 138328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15748166-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2061C>T	p.Ser687Ser	splice_region_variant, synonymous_variant	17/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2082C>T	p.Ser694Ser	splice_region_variant, synonymous_variant	18/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2082C>T	p.Ser694Ser	splice_region_variant, synonymous_variant	18/42		NP_001035203.1
MYH11	NM_022844.3	c.2061C>T	p.Ser687Ser	splice_region_variant, synonymous_variant	17/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2061C>T	p.Ser687Ser	splice_region_variant, synonymous_variant	17/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2082C>T	p.Ser694Ser	splice_region_variant, synonymous_variant	18/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9583 AN: 152160 Hom.: 337 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0677

Gnomad OTH AF: 0.0692

GnomAD3 exomes AF: 0.0649 AC: 16247 AN: 250184 Hom.: 741 AF XY: 0.0660 AC XY: 8941 AN XY: 135424

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0902

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.0296

Gnomad NFE exome AF: 0.0634

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0678 AC: 99136 AN: 1461296 Hom.: 3798 Cov.: 34 AF XY: 0.0680 AC XY: 49460 AN XY: 726944

Gnomad4 AFR exome AF: 0.0528

Gnomad4 AMR exome AF: 0.0304

Gnomad4 ASJ exome AF: 0.0894

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.0646

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0677

Gnomad4 OTH exome AF: 0.0783

GnomAD4 genome AF: 0.0630 AC: 9586 AN: 152278 Hom.: 335 Cov.: 32 AF XY: 0.0606 AC XY: 4513 AN XY: 74462

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.0460

Gnomad4 ASJ AF: 0.0853

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.0702

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0676

Gnomad4 OTH AF: 0.0681

Alfa AF: 0.0686 Hom.: 179

Bravo AF: 0.0638

Asia WGS AF: 0.117 AC: 407 AN: 3478

EpiCase AF: 0.0677

EpiControl AF: 0.0616

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ser694Ser 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 6.7% (576/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs880071). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 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	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

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	Ambry Genetics	Feb 26, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

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	-0.95
CADD	Benign	0.0040
DANN	Benign	0.46

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: rs880071; hg19: chr16-15842023; COSMIC: COSV55545525; COSMIC: COSV55545525;