16-15750181-G-T

Variant names:

• chr16-15750181-G-T
• rs749498320
• NM_002474.3:c.2015C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002474.3(MYH11):​c.2015C>A​(p.Thr672Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T672M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2015C>A	p.Thr672Lys	missense_variant	Exon 16 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2036C>A	p.Thr679Lys	missense_variant	Exon 17 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2036C>A	p.Thr679Lys	missense_variant	Exon 17 of 42		NP_001035203.1
MYH11	NM_022844.3	c.2015C>A	p.Thr672Lys	missense_variant	Exon 16 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2015C>A	p.Thr672Lys	missense_variant	Exon 16 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2036C>A	p.Thr679Lys	missense_variant	Exon 17 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;.;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	.;.;L;L
PhyloP100		4.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.34	N;N;.;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.028	D;D;.;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.0040	.;.;.;B
Vest4		0.56
MutPred		0.61		.;.;Gain of methylation at T672 (P = 0.0168);Gain of methylation at T672 (P = 0.0168);
MVP		0.80
MPC		1.1
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.093
gMVP		0.65
Mutation Taster		=84/16	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: rs749498320; hg19: chr16-15844038;