16-15745177-G-A

Position:

• chr16-15745177-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.2472C>T​(p.Ala824Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,450 control chromosomes in the GnomAD database, including 86,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6049 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80739 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.295

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=-0.62).
• BP6: Variant 16-15745177-G-A is Benign according to our data. Variant chr16-15745177-G-A is described in ClinVar as [Benign]. Clinvar id is 138330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15745177-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2472C>T	p.Ala824Ala	synonymous_variant	20/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2493C>T	p.Ala831Ala	synonymous_variant	21/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2493C>T	p.Ala831Ala	synonymous_variant	21/42		NP_001035203.1
MYH11	NM_022844.3	c.2472C>T	p.Ala824Ala	synonymous_variant	20/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2472C>T	p.Ala824Ala	synonymous_variant	20/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2493C>T	p.Ala831Ala	synonymous_variant	21/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40622 AN: 151960 Hom.: 6050 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.299 AC: 75207 AN: 251320 Hom.: 11895 AF XY: 0.298 AC XY: 40528 AN XY: 135842

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.402

Gnomad SAS exome AF: 0.247

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.327 AC: 478574 AN: 1461372 Hom.: 80739 Cov.: 43 AF XY: 0.325 AC XY: 236597 AN XY: 727010

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.274

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.312

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.267 AC: 40629 AN: 152078 Hom.: 6049 Cov.: 32 AF XY: 0.265 AC XY: 19710 AN XY: 74300

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.260

Alfa AF: 0.269 Hom.: 2720

Bravo AF: 0.260

Asia WGS AF: 0.319 AC: 1110 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.309

ClinVar

Significance: Benign

Submissions summary: Benign:14

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	Oct 03, 2024	- -
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 19, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 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	Ala831Ala in exon 21 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 32.2% (2769/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1050113). -

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	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.62
CADD	Benign	8.1
DANN	Benign	0.87

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: rs1050113; hg19: chr16-15839034; COSMIC: COSV55543873; COSMIC: COSV55543873;