rs28570191

Variant names:

• chr16-15838118-G-A
• rs28570191
• NM_002474.3:c.135C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):​c.135C>T​(p.Phe45Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0089 in 1,613,950 control chromosomes in the GnomAD database, including 780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (409 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (371 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0770

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-15838118-G-A is Benign according to our data. Variant chr16-15838118-G-A is described in ClinVar as [Benign]. Clinvar id is 138363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15838118-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.077 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.135C>T	p.Phe45Phe	synonymous_variant	Exon 2 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.135C>T	p.Phe45Phe	synonymous_variant	Exon 2 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.135C>T	p.Phe45Phe	synonymous_variant	Exon 2 of 42		NP_001035203.1
MYH11	NM_022844.3	c.135C>T	p.Phe45Phe	synonymous_variant	Exon 2 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.135C>T	p.Phe45Phe	synonymous_variant	Exon 2 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.135C>T	p.Phe45Phe	synonymous_variant	Exon 2 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6037 AN: 151968 Hom.: 408 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0124 AC: 3117 AN: 251064 Hom.: 166 AF XY: 0.00920 AC XY: 1249 AN XY: 135720

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.00841

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00569 AC: 8316 AN: 1461864 Hom.: 371 Cov.: 32 AF XY: 0.00499 AC XY: 3628 AN XY: 727236

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.00865

Gnomad4 ASJ exome AF: 0.0310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0398 AC: 6055 AN: 152086 Hom.: 409 Cov.: 31 AF XY: 0.0377 AC XY: 2799 AN XY: 74322

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0222 Hom.: 111

Bravo AF: 0.0463

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Phe45Phe in exon 2 of MYH11: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 13.5% (591/4394) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs28570191). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Nov 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.7
DANN	Benign	0.75

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: rs28570191; hg19: chr16-15931975;