16-15745177-G-A

Variant names:

• chr16-15745177-G-A
• rs1050113
• NM_002474.3:c.2472C>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.2472C>T​(p.Ala824Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,450 control chromosomes in the GnomAD database, including 86,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A824A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6049 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80739 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.295
• Publications: 21 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=-0.62).
• BP6: Variant 16-15745177-G-A is Benign according to our data. Variant chr16-15745177-G-A is described in ClinVar as Benign. ClinVar VariationId is 138330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 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.2472C>T	p.Ala824Ala	synonymous	Exon 20 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.2493C>T	p.Ala831Ala	synonymous	Exon 21 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.2493C>T	p.Ala831Ala	synonymous	Exon 21 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.2472C>T	p.Ala824Ala	synonymous	Exon 20 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.2493C>T	p.Ala831Ala	synonymous	Exon 21 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.2493C>T	p.Ala831Ala	synonymous	Exon 21 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40622 AN: 151960 Hom.: 6050 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.260

GnomAD2 exomes AF: 0.299 AC: 75207 AN: 251320 AF XY: 0.298

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.327 AC: 478574 AN: 1461372 Hom.: 80739 Cov.: 43 AF XY: 0.325 AC XY: 236597 AN XY: 727010

African (AFR) AF: 0.131 AC: 4390 AN: 33474

American (AMR) AF: 0.274 AC: 12240 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6257 AN: 26134

East Asian (EAS) AF: 0.431 AC: 17086 AN: 39688

South Asian (SAS) AF: 0.251 AC: 21640 AN: 86236

European-Finnish (FIN) AF: 0.312 AC: 16664 AN: 53338

Middle Eastern (MID) AF: 0.194 AC: 1119 AN: 5766

European-Non Finnish (NFE) AF: 0.342 AC: 380326 AN: 1111646

Other (OTH) AF: 0.312 AC: 18852 AN: 60382

GnomAD4 genome AF: 0.267 AC: 40629 AN: 152078 Hom.: 6049 Cov.: 32 AF XY: 0.265 AC XY: 19710 AN XY: 74300

African (AFR) AF: 0.136 AC: 5653 AN: 41506

American (AMR) AF: 0.271 AC: 4131 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 803 AN: 3472

East Asian (EAS) AF: 0.397 AC: 2045 AN: 5146

South Asian (SAS) AF: 0.260 AC: 1251 AN: 4818

European-Finnish (FIN) AF: 0.306 AC: 3235 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22776 AN: 67978

Other (OTH) AF: 0.260 AC: 548 AN: 2110

Alfa AF: 0.280 Hom.: 4765

Bravo AF: 0.260

Asia WGS AF: 0.319 AC: 1110 AN: 3478

EpiCase AF: 0.313

EpiControl AF: 0.309

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	4	not specified (4)
-	-	3	Aortic aneurysm, familial thoracic 4 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (1)
-	-	1	not provided (1)
-	-	1	Visceral myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.1
DANN	Benign	0.87
PhyloP100		-0.29
Mutation Taster		=95/5	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: rs1050113; hg19: chr16-15839034; COSMIC: COSV55543873; COSMIC: COSV55543873;