16-15718341-C-T

Position:

• chr16-15718341-C-T

Variant summary

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

The NM_002474.3(MYH11):​c.5269G>A​(p.Asp1757Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000435 in 1,608,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1757E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.67

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]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

MYH11 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5269G>A	p.Asp1757Asn	missense_variant	37/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5290G>A	p.Asp1764Asn	missense_variant	38/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-5850C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5269G>A	p.Asp1757Asn	missense_variant	37/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5290G>A	p.Asp1764Asn	missense_variant	38/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-5850C>T		intron_variant		1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000404 AC: 10 AN: 247496 Hom.: 0 AF XY: 0.0000373 AC XY: 5 AN XY: 134084

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000545

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000323 AC: 47 AN: 1456750 Hom.: 0 Cov.: 31 AF XY: 0.0000304 AC XY: 22 AN XY: 724828

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74334

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

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	Ambry Genetics	Jan 10, 2023	The p.D1757N variant (also known as c.5269G>A), located in coding exon 36 of the MYH11 gene, results from a G to A substitution at nucleotide position 5269. The aspartic acid at codon 1757 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This missense variant replaces aspartic acid with asparagine at codon 1764 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/278868 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. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1764 of the MYH11 protein (p.Asp1764Asn). This variant is present in population databases (rs752996609, gnomAD 0.03%). 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: 201083). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

Sep 16, 2015

The D1757N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been seen in multiple individuals referred for TAAD testing at GeneDx. Furthermore, the D1757N 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. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, additional evidence is needed to determine whether this variant is pathogenic or benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	.;.;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.5	.;.;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D;D;.;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.59
MVP		0.87
MPC		0.52
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.60
gMVP		0.34

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: rs752996609; hg19: chr16-15812198;