chr16-15771667-T-C

Position:

• chr16-15771667-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_002474.3(MYH11):​c.935A>G​(p.Asn312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.92

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 Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2926076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.935A>G	p.Asn312Ser	missense_variant	9/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.956A>G	p.Asn319Ser	missense_variant	10/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.956A>G	p.Asn319Ser	missense_variant	10/42		NP_001035203.1
MYH11	NM_022844.3	c.935A>G	p.Asn312Ser	missense_variant	9/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.935A>G	p.Asn312Ser	missense_variant	9/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.956A>G	p.Asn319Ser	missense_variant	10/43	1	NM_001040113.2	ENSP00000407821

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152070 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251452 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152070 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74298

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2022	This missense variant replaces asparagine with serine at codon 319 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with abdominal aortic aneurysm, but this variant did not segregate with disease in the family (PMID: 26017485). This variant has been identified in 13/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 16, 2021	The p.N312S variant (also known as c.935A>G), located in coding exon 8 of the MYH11 gene, results from an A to G substitution at nucleotide position 935. The asparagine at codon 312 is replaced by serine, an amino acid with highly similar properties. This variant (reported as c.956A>G, p.N319S) has been detected in a family reported to have abdominal aortic aneurysm; however, it was indicated to not segregate with disease (van de Luijtgaarden KM et al. Hum Genet, 2015 Aug;134:881-93). This variant co-occurred with a pathogenic alteration in the TGFBR1 gene in a family with thoracic aortic aneurysm or dissection. The TGFBR1 mutation segregated with disease in the family (Dong SB et al. Ann Vasc Surg, 2014 Nov;28:1909-12). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	Reported as N319S (due to alternate nomenclature) in an individual with abdominal aortic aneurysm; however, no additional clinical information was available (van de Luijtgaarden et al., 2015); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 566653; Landrum et al., 2016); Observed in 13/282,798 (0.0046%) global alleles in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26017485) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 12, 2022	The MYH11 c.935A>G; p.Asn312Ser variant (rs149964928), also known as p.Asn319Ser on an alternate transcript, is reported in an individual with abdominal aortic aneurysm, but did not segregate with disease in the family (van de Luijtgaarden 2015). The variant is listed in the ClinVar database (Variation ID: 566653) and is reported in the general population with an overall allele frequency of 0.005% (13/282798 alleles) in the Genome Aggregation Database. The asparagine at codon 312 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.381). Due to limited information, the clinical significance of the p.Asn312Ser variant is uncertain at this time. References: van de Luijtgaarden KM et al. First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. Hum Genet. 2015 Aug;134(8):881-93. PMID: 26017485. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 319 of the MYH11 protein (p.Asn319Ser). This variant is present in population databases (rs149964928, gnomAD 0.01%). This missense change has been observed in individual(s) with abdominal aneurysm (PMID: 26017485). ClinVar contains an entry for this variant (Variation ID: 566653). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;.;D
Eigen	Benign	-0.11
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.2	.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;.;D
REVEL	Uncertain	0.38
Sift	Benign	0.049	D;D;.;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.10
MVP		0.73
MPC		0.60
ClinPred		0.098	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149964928; hg19: chr16-15865524;