rs149964928

Variant names:

• chr16-15771667-T-C
• rs149964928
• NM_002474.3:c.935A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_002474.3(MYH11):​c.935A>G​(p.Asn312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N312K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.92
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2926076).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000397 (58/1461890) while in subpopulation SAS AF = 0.0000464 (4/86258). AF 95% confidence interval is 0.0000346. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.935A>G	p.Asn312Ser	missense	Exon 9 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.956A>G	p.Asn319Ser	missense	Exon 10 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.956A>G	p.Asn319Ser	missense	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.935A>G	p.Asn312Ser	missense	Exon 9 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.956A>G	p.Asn319Ser	missense	Exon 10 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.956A>G	p.Asn319Ser	missense	Exon 10 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152070 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251452 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152070 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74298

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000386 Hom.: 0

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Aortic aneurysm, familial thoracic 4 (2)
-	2	-	Familial thoracic aortic aneurysm and aortic dissection (2)
-	2	-	not provided (2)
-	1	-	Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.11
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.38
Sift	Benign	0.049	D
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.73
MPC		0.60
ClinPred		0.098	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.18
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149964928; hg19: chr16-15865524;