16-15756347-A-G

Variant names:

• chr16-15756347-A-G
• rs2272554
• NM_002474.3:c.1743T>C

Variant summary

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

The NM_001040114.2(MYH11):​c.1764T>C​(p.Ala588Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,613,510 control chromosomes in the GnomAD database, including 157,746 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. A588A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.49 (19863 hom., cov: 32)
  • Exomes 𝑓: 0.43 (137883 hom.)
• Consequence: MYH11 NM_001040114.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.675
• Publications: 24 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-15756347-A-G is Benign according to our data. Variant chr16-15756347-A-G is described in ClinVar as Benign. ClinVar VariationId is 138327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.675 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040114.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.1743T>C	p.Ala581Ala	synonymous	Exon 14 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.1764T>C	p.Ala588Ala	synonymous	Exon 15 of 43	NP_001035202.1
	MYH11	NM_001040114.2		c.1764T>C	p.Ala588Ala	synonymous	Exon 15 of 42	NP_001035203.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.1743T>C	p.Ala581Ala	synonymous	Exon 14 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.1764T>C	p.Ala588Ala	synonymous	Exon 15 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.1764T>C	p.Ala588Ala	synonymous	Exon 15 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74927 AN: 151842 Hom.: 19824 Cov.: 32

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.436 AC: 109390 AN: 250808 AF XY: 0.429

Gnomad AFR exome AF: 0.691

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.701

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.429 AC: 626814 AN: 1461550 Hom.: 137883 Cov.: 54 AF XY: 0.427 AC XY: 310357 AN XY: 727064

African (AFR) AF: 0.689 AC: 23056 AN: 33472

American (AMR) AF: 0.356 AC: 15887 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 10221 AN: 26132

East Asian (EAS) AF: 0.687 AC: 27264 AN: 39692

South Asian (SAS) AF: 0.396 AC: 34161 AN: 86246

European-Finnish (FIN) AF: 0.387 AC: 20666 AN: 53402

Middle Eastern (MID) AF: 0.314 AC: 1803 AN: 5738

European-Non Finnish (NFE) AF: 0.420 AC: 466762 AN: 1111806

Other (OTH) AF: 0.447 AC: 26994 AN: 60382

GnomAD4 genome AF: 0.494 AC: 75022 AN: 151960 Hom.: 19863 Cov.: 32 AF XY: 0.491 AC XY: 36444 AN XY: 74278

African (AFR) AF: 0.687 AC: 28450 AN: 41438

American (AMR) AF: 0.403 AC: 6152 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1336 AN: 3470

East Asian (EAS) AF: 0.688 AC: 3543 AN: 5146

South Asian (SAS) AF: 0.422 AC: 2033 AN: 4818

European-Finnish (FIN) AF: 0.380 AC: 4013 AN: 10560

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28212 AN: 67952

Other (OTH) AF: 0.456 AC: 962 AN: 2110

Alfa AF: 0.436 Hom.: 71857

Bravo AF: 0.503

Asia WGS AF: 0.553 AC: 1921 AN: 3478

EpiCase AF: 0.398

EpiControl AF: 0.393

ClinVar

ClinVar submissions as Germline

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	-0.83
CADD	Benign	0.10
DANN	Benign	0.56
PhyloP100		-0.68
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: rs2272554; hg19: chr16-15850204; COSMIC: COSV55543893;