rs587781079

Variant names:

• chr16-15776175-A-G
• rs34341838
• NM_002474.3:c.792T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-15776175-A-G
• chrNT_187607.1-1434160-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):​c.792T>C​(p.Tyr264Tyr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,611,816 control chromosomes in the GnomAD database, including 1,344 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (92 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1252 hom.)
• Consequence: MYH11 NM_002474.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004735
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.20
• Publications: 7 publications found

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]

MYH11 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-15776175-A-G is Benign according to our data. Variant chr16-15776175-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0291 (4431/152206) while in subpopulation NFE AF = 0.0453 (3079/68022). AF 95% confidence interval is 0.0439. There are 92 homozygotes in GnomAd4. There are 2161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.792T>C	p.Tyr264Tyr	splice_region_variant, synonymous_variant	Exon 8 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.813T>C	p.Tyr271Tyr	splice_region_variant, synonymous_variant	Exon 9 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.813T>C	p.Tyr271Tyr	splice_region_variant, synonymous_variant	Exon 9 of 42		NP_001035203.1
MYH11	NM_022844.3	c.792T>C	p.Tyr264Tyr	splice_region_variant, synonymous_variant	Exon 8 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.792T>C	p.Tyr264Tyr	splice_region_variant, synonymous_variant	Exon 8 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.813T>C	p.Tyr271Tyr	splice_region_variant, synonymous_variant	Exon 9 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4432 AN: 152088 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.00746

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0292 AC: 7339 AN: 251464 AF XY: 0.0290

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0405

Gnomad NFE exome AF: 0.0459

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0371 AC: 54186 AN: 1459610 Hom.: 1252 Cov.: 30 AF XY: 0.0363 AC XY: 26377 AN XY: 726284

African (AFR) AF: 0.00658 AC: 220 AN: 33446

American (AMR) AF: 0.0173 AC: 772 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 536 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00634 AC: 547 AN: 86226

European-Finnish (FIN) AF: 0.0434 AC: 2318 AN: 53412

Middle Eastern (MID) AF: 0.0336 AC: 194 AN: 5768

European-Non Finnish (NFE) AF: 0.0429 AC: 47645 AN: 1109886

Other (OTH) AF: 0.0323 AC: 1951 AN: 60320

GnomAD4 genome AF: 0.0291 AC: 4431 AN: 152206 Hom.: 92 Cov.: 32 AF XY: 0.0290 AC XY: 2161 AN XY: 74424

African (AFR) AF: 0.00744 AC: 309 AN: 41516

American (AMR) AF: 0.0268 AC: 410 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.0412 AC: 437 AN: 10600

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0453 AC: 3079 AN: 68022

Other (OTH) AF: 0.0280 AC: 59 AN: 2110

Alfa AF: 0.0362 Hom.: 151

Bravo AF: 0.0263

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.0417

EpiControl AF: 0.0439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:5

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tyr271Tyr in exon 9 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 4.2% (364/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs34341838). -

Nov 29, 2012

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 10, 2023

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype Benign:1

Dec 23, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.53
CADD	Benign	9.6
DANN	Benign	0.63
PhyloP100		2.2
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34341838; hg19: chr16-15870032; COSMIC: COSV55553779;