16-15759739-C-G

Variant names:

• chr16-15759739-C-G
• rs2280764
• NM_002474.3:c.1249-11G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002474.3(MYH11):​c.1249-11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,613,218 control chromosomes in the GnomAD database, including 136,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18149 hom., cov: 32)
  • Exomes 𝑓: 0.39 (117852 hom.)
• Consequence: MYH11 NM_002474.3 intron
• Scores: Splicing: ADA: 0.00003464
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.720
• Publications: 12 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)

LOC124903650 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-15759739-C-G is Benign according to our data. Variant chr16-15759739-C-G is described in ClinVar as Benign. ClinVar VariationId is 138371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.1249-11G>C		intron_variant	Intron 11 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.1270-11G>C		intron_variant	Intron 12 of 42	ENST00000452625.7	NP_001035202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.1249-11G>C		intron_variant	Intron 11 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.1270-11G>C		intron_variant	Intron 12 of 42	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70999 AN: 151934 Hom.: 18110 Cov.: 32

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.438

GnomAD2 exomes AF: 0.411 AC: 103052 AN: 250574 AF XY: 0.405

Gnomad AFR exome AF: 0.677

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.694

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.395 AC: 576816 AN: 1461166 Hom.: 117852 Cov.: 45 AF XY: 0.394 AC XY: 286661 AN XY: 726898

African (AFR) AF: 0.674 AC: 22543 AN: 33464

American (AMR) AF: 0.345 AC: 15400 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 9998 AN: 26132

East Asian (EAS) AF: 0.680 AC: 27008 AN: 39692

South Asian (SAS) AF: 0.408 AC: 35187 AN: 86222

European-Finnish (FIN) AF: 0.339 AC: 18092 AN: 53408

Middle Eastern (MID) AF: 0.312 AC: 1735 AN: 5560

European-Non Finnish (NFE) AF: 0.379 AC: 421584 AN: 1111680

Other (OTH) AF: 0.419 AC: 25269 AN: 60338

GnomAD4 genome AF: 0.468 AC: 71095 AN: 152052 Hom.: 18149 Cov.: 32 AF XY: 0.465 AC XY: 34546 AN XY: 74318

African (AFR) AF: 0.671 AC: 27833 AN: 41466

American (AMR) AF: 0.389 AC: 5942 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1312 AN: 3472

East Asian (EAS) AF: 0.681 AC: 3513 AN: 5156

South Asian (SAS) AF: 0.431 AC: 2075 AN: 4818

European-Finnish (FIN) AF: 0.339 AC: 3578 AN: 10564

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25589 AN: 67976

Other (OTH) AF: 0.442 AC: 934 AN: 2114

Alfa AF: 0.410 Hom.: 2452

Bravo AF: 0.479

Asia WGS AF: 0.546 AC: 1899 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 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 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1270-11G>C in intron 12 of MYH11: This variant is not expected to have clinical significance because it has been identified in 37.3% (3209/8600) of European Ame rican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2280764). -

Aortic aneurysm, familial thoracic 4 Benign:3

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Visceral myopathy 2 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

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	-0.85
CADD	Benign	3.2
DANN	Benign	0.41
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs2280764; hg19: chr16-15853596; COSMIC: COSV55543530;