16-15745203-T-C

Variant names:

• chr16-15745203-T-C
• rs1243566183
• NM_002474.3:c.2446A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_002474.3(MYH11):​c.2446A>G​(p.Met816Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,594 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M816L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (1 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000137 (2/1461594) while in subpopulation MID AF = 0.000347 (2/5764). AF 95% confidence interval is 0.000061. There are 1 homozygotes in GnomAdExome4. There are 0 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2446A>G	p.Met816Val	missense_variant	Exon 20 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2467A>G	p.Met823Val	missense_variant	Exon 21 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2467A>G	p.Met823Val	missense_variant	Exon 21 of 42		NP_001035203.1
MYH11	NM_022844.3	c.2446A>G	p.Met816Val	missense_variant	Exon 20 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2446A>G	p.Met816Val	missense_variant	Exon 20 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2467A>G	p.Met823Val	missense_variant	Exon 21 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461594 Hom.: 1 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;.;T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	.;.;L;L
PhyloP100		5.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.80	N;N;.;N
REVEL	Benign	0.19
Sift	Uncertain	0.011	D;D;.;D
Sift4G	Benign	0.084	T;T;T;T
Polyphen		0.011	.;.;.;B
Vest4		0.75
MutPred		0.50		.;.;Loss of stability (P = 0.0495);Loss of stability (P = 0.0495);
MVP		0.76
MPC		1.2
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.41
gMVP		0.74
Mutation Taster		=90/10	polymorphism

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: rs1243566183; hg19: chr16-15839060;