16-15837962-G-T

Variant names:

• chr16-15837962-G-T
• rs113363750
• NM_002474.3:c.291C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002474.3(MYH11):​c.291C>A​(p.Asn97Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N97S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0300
• Publications: 1 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.291C>A	p.Asn97Lys	missense_variant	Exon 2 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.291C>A	p.Asn97Lys	missense_variant	Exon 2 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.291C>A	p.Asn97Lys	missense_variant	Exon 2 of 42		NP_001035203.1
MYH11	NM_022844.3	c.291C>A	p.Asn97Lys	missense_variant	Exon 2 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.291C>A	p.Asn97Lys	missense_variant	Exon 2 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.291C>A	p.Asn97Lys	missense_variant	Exon 2 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Dec 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the myosin motor domain of the MYH11 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;.;D
Eigen	Benign	-0.0039
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.9	H;H;H;H
PhyloP100		0.030
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D;D;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.96
MutPred		0.86		Loss of catalytic residue at N97 (P = 0.0222);Loss of catalytic residue at N97 (P = 0.0222);Loss of catalytic residue at N97 (P = 0.0222);Loss of catalytic residue at N97 (P = 0.0222);
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		-6.9
Varity_R		0.67
gMVP		0.84
Mutation Taster		=16/84	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: rs113363750; hg19: chr16-15931819;