chr16-15747916-G-A

Variant names:

• chr16-15747916-G-A
• rs12931799
• NM_002474.3:c.2208C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002474.3(MYH11):​c.2208C>T​(p.Ile736Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,613,904 control chromosomes in the GnomAD database, including 2,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (603 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1901 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.387
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 16-15747916-G-A is Benign according to our data. Variant chr16-15747916-G-A is described in ClinVar as Benign. ClinVar VariationId is 36616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.387 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 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.2208C>T	p.Ile736Ile	synonymous	Exon 18 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.2229C>T	p.Ile743Ile	synonymous	Exon 19 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.2229C>T	p.Ile743Ile	synonymous	Exon 19 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.2208C>T	p.Ile736Ile	synonymous	Exon 18 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.2229C>T	p.Ile743Ile	synonymous	Exon 19 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.2229C>T	p.Ile743Ile	synonymous	Exon 19 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0727 AC: 11039 AN: 151914 Hom.: 595 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0524

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0662

GnomAD2 exomes AF: 0.0529 AC: 13315 AN: 251468 AF XY: 0.0538

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.0295

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0419 AC: 61240 AN: 1461872 Hom.: 1901 Cov.: 34 AF XY: 0.0431 AC XY: 31314 AN XY: 727238

African (AFR) AF: 0.147 AC: 4935 AN: 33480

American (AMR) AF: 0.0304 AC: 1361 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 691 AN: 26136

East Asian (EAS) AF: 0.107 AC: 4232 AN: 39700

South Asian (SAS) AF: 0.0889 AC: 7672 AN: 86258

European-Finnish (FIN) AF: 0.0365 AC: 1951 AN: 53404

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.0333 AC: 37082 AN: 1112006

Other (OTH) AF: 0.0512 AC: 3090 AN: 60396

GnomAD4 genome AF: 0.0729 AC: 11076 AN: 152032 Hom.: 603 Cov.: 31 AF XY: 0.0737 AC XY: 5476 AN XY: 74304

African (AFR) AF: 0.147 AC: 6090 AN: 41428

American (AMR) AF: 0.0523 AC: 798 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3470

East Asian (EAS) AF: 0.107 AC: 552 AN: 5146

South Asian (SAS) AF: 0.101 AC: 485 AN: 4806

European-Finnish (FIN) AF: 0.0367 AC: 389 AN: 10604

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2417 AN: 67994

Other (OTH) AF: 0.0722 AC: 152 AN: 2106

Alfa AF: 0.0472 Hom.: 470

Bravo AF: 0.0763

Asia WGS AF: 0.0980 AC: 339 AN: 3478

EpiCase AF: 0.0348

EpiControl AF: 0.0342

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	Aortic aneurysm, familial thoracic 4 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial aortopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.1
DANN	Benign	0.78
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12931799; hg19: chr16-15841773; COSMIC: COSV55555025; COSMIC: COSV55555025;