16-15745203-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH11

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.2446A>G	p.Met816Val	missense_variant	20/41	ENST00000300036.6
MYH11	NM_001040113.2	c.2467A>G	p.Met823Val	missense_variant	21/43	ENST00000452625.7
MYH11	NM_001040114.2	c.2467A>G	p.Met823Val	missense_variant	21/42
MYH11	NM_022844.3	c.2446A>G	p.Met816Val	missense_variant	20/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.2446A>G	p.Met816Val	missense_variant	20/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.2467A>G	p.Met823Val	missense_variant	21/43	1	NM_001040113.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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
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
MutationTaster	Benign	1.0	D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1243566183; hg19: chr16-15839060;