rs34341838

Positions:

• chr16-15776175-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):​c.792T>C​(p.Tyr264=) 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:14
• Conservation: PhyloP100: 2.20

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 -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 [Likely_benign]. Clinvar id is 138368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15776175-A-G is described in Lovd as [Benign]. Variant chr16-15776175-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 92 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.792T>C	p.Tyr264=	splice_region_variant, synonymous_variant	8/41	ENST00000300036.6
MYH11	NM_001040113.2	c.813T>C	p.Tyr271=	splice_region_variant, synonymous_variant	9/43	ENST00000452625.7
MYH11	NM_001040114.2	c.813T>C	p.Tyr271=	splice_region_variant, synonymous_variant	9/42
MYH11	NM_022844.3	c.792T>C	p.Tyr264=	splice_region_variant, synonymous_variant	8/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.792T>C	p.Tyr264=	splice_region_variant, synonymous_variant	8/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.813T>C	p.Tyr271=	splice_region_variant, synonymous_variant	9/43	1	NM_001040113.2

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

GnomAD3 exomes AF: 0.0292 AC: 7339 AN: 251464 Hom.: 169 AF XY: 0.0290 AC XY: 3940 AN XY: 135902

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 SAS exome AF: 0.00532

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

Gnomad4 AFR exome AF: 0.00658

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00634

Gnomad4 FIN exome AF: 0.0434

Gnomad4 NFE exome AF: 0.0429

Gnomad4 OTH exome AF: 0.0323

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

Gnomad4 AFR AF: 0.00744

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0453

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0369 Hom.: 99

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	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). -
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	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 25, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 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	-0.53
CADD	Benign	9.6
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

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