chr16-15786662-A-G

Variant names:

• chr16-15786662-A-G
• rs773450359
• NM_002474.3:c.601T>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.601T>C​(p.Ser201Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S201A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• 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, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.601T>C	p.Ser201Pro	missense_variant	Exon 5 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.601T>C	p.Ser201Pro	missense_variant	Exon 5 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.601T>C	p.Ser201Pro	missense_variant	Exon 5 of 42		NP_001035203.1
MYH11	NM_022844.3	c.601T>C	p.Ser201Pro	missense_variant	Exon 5 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.601T>C	p.Ser201Pro	missense_variant	Exon 5 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.601T>C	p.Ser201Pro	missense_variant	Exon 5 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.8	L;L;L;L
PhyloP100		9.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.026	D;D;.;D
Sift4G	Uncertain	0.046	D;D;T;D
Polyphen		0.97	.;.;.;D
Vest4		0.76
MutPred		0.49		Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);
MVP		0.98
MPC		2.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.95
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs773450359; hg19: chr16-15880519;