NM_002474.3:c.987C>T

Variant names:

• chr16-15771615-G-A
• rs4781689
• NM_002474.3:c.987C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):​c.987C>T​(p.Thr329Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0962 in 1,613,660 control chromosomes in the GnomAD database, including 8,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T329T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.080 (700 hom., cov: 29)
  • Exomes 𝑓: 0.098 (7962 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0670
• Publications: 14 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, Unknown 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• visceral myopathy 2

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-15771615-G-A is Benign according to our data. Variant chr16-15771615-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.067 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.987C>T	p.Thr329Thr	synonymous	Exon 9 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.1008C>T	p.Thr336Thr	synonymous	Exon 10 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.1008C>T	p.Thr336Thr	synonymous	Exon 10 of 42	NP_001035203.1	P35749-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.987C>T	p.Thr329Thr	synonymous	Exon 9 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.1008C>T	p.Thr336Thr	synonymous	Exon 10 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.1008C>T	p.Thr336Thr	synonymous	Exon 10 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12201 AN: 151706 Hom.: 696 Cov.: 29

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0702

Gnomad EAS AF: 0.00387

Gnomad SAS AF: 0.0985

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0681

GnomAD2 exomes AF: 0.107 AC: 26978 AN: 251460 AF XY: 0.105

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.0769

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.0996

Gnomad OTH exome AF: 0.0979

GnomAD4 exome AF: 0.0978 AC: 142950 AN: 1461836 Hom.: 7962 Cov.: 33 AF XY: 0.0977 AC XY: 71016 AN XY: 727218

African (AFR) AF: 0.0163 AC: 545 AN: 33480

American (AMR) AF: 0.197 AC: 8810 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 1912 AN: 26136

East Asian (EAS) AF: 0.00640 AC: 254 AN: 39700

South Asian (SAS) AF: 0.102 AC: 8796 AN: 86256

European-Finnish (FIN) AF: 0.165 AC: 8792 AN: 53420

Middle Eastern (MID) AF: 0.0597 AC: 344 AN: 5764

European-Non Finnish (NFE) AF: 0.0975 AC: 108469 AN: 1111970

Other (OTH) AF: 0.0833 AC: 5028 AN: 60388

GnomAD4 genome AF: 0.0805 AC: 12216 AN: 151824 Hom.: 700 Cov.: 29 AF XY: 0.0857 AC XY: 6359 AN XY: 74184

African (AFR) AF: 0.0191 AC: 791 AN: 41446

American (AMR) AF: 0.114 AC: 1736 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0702 AC: 243 AN: 3460

East Asian (EAS) AF: 0.00388 AC: 20 AN: 5158

South Asian (SAS) AF: 0.0995 AC: 478 AN: 4806

European-Finnish (FIN) AF: 0.179 AC: 1878 AN: 10494

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6868 AN: 67914

Other (OTH) AF: 0.0670 AC: 141 AN: 2106

Alfa AF: 0.0918 Hom.: 1416

Bravo AF: 0.0734

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0885

EpiControl AF: 0.0887

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Aortic aneurysm, familial thoracic 4 (4)
-	-	4	not specified (4)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.3
DANN	Benign	0.45
PhyloP100		-0.067
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4781689; hg19: chr16-15865472;