rs1555560373

Variant names:

• chr16-15747902-A-G
• rs1555560373
• NM_002474.3:c.2222T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002474.3(MYH11):​c.2222T>C​(p.Met741Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.2222T>C	p.Met741Thr	missense_variant	Exon 18 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.2243T>C	p.Met748Thr	missense_variant	Exon 19 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.2243T>C	p.Met748Thr	missense_variant	Exon 19 of 42		NP_001035203.1
MYH11	NM_022844.3	c.2222T>C	p.Met741Thr	missense_variant	Exon 18 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.2222T>C	p.Met741Thr	missense_variant	Exon 18 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.2243T>C	p.Met748Thr	missense_variant	Exon 19 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital aneurysm of ascending aorta Uncertain:1

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of familial thoracic aortic aneurysm. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;.;.;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.94	.;.;L;L
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.040	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.84
MutPred		0.51		.;.;Loss of stability (P = 0.0533);Loss of stability (P = 0.0533);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.81
Mutation Taster		=10/90	disease causing

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: rs1555560373; hg19: chr16-15841759;