chr16-15837962-G-C

Position:

• chr16-15837962-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002474.3(MYH11):​c.291C>G​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. N97N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0300

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 Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.291C>G	p.Asn97Lys	missense_variant	2/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.291C>G	p.Asn97Lys	missense_variant	2/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.291C>G	p.Asn97Lys	missense_variant	2/42		NP_001035203.1
MYH11	NM_022844.3	c.291C>G	p.Asn97Lys	missense_variant	2/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.291C>G	p.Asn97Lys	missense_variant	2/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.291C>G	p.Asn97Lys	missense_variant	2/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 14, 2024

- -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2024

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 97 of the MYH11 protein (p.Asn97Lys). This variant is present in population databases (rs113363750, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 201096). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2014

p.Asn97Lys (N97K) AAC>AAG: c.291 C>G in exon 2 of the MYH11 gene (NM_002474.2). The N97K variant in the MYH11 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The N97K variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. The Asparagine97 residue is conserved across species. In silico analysis predicts N97K is damaging to the protein structure/function. The N97K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, no mutations in nearby residues have been reported in association with TAAD, suggesting this region of the protein may be tolerant to change. Therefore, based on the currently available information, it is unclear whether these variants are pathogenic mutations or rare benign variants. The variant is found in TAAD panel(s). -

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	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.9	H;H;H;H
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		0.94	D
GERP RS		-6.9
Varity_R		0.67
gMVP		0.84

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: rs113363750; hg19: chr16-15931819;