rs1029371842

Positions:

• chr16-15718395-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The ENST00000300036.6(MYH11):​c.5215G>A​(p.Ala1739Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,446,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. A1739P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYH11 ENST00000300036.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.361

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]

ACMG classification

Verdict is Likely_benign. 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09647423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5215G>A	p.Ala1739Thr	missense_variant	37/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5236G>A	p.Ala1746Thr	missense_variant	38/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-5796C>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.5215G>A	p.Ala1739Thr	missense_variant	37/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.5236G>A	p.Ala1746Thr	missense_variant	38/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.948-5796C>T		intron_variant		1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000436 AC: 1 AN: 229570 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124610

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: 0.00000972

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1446676 Hom.: 0 Cov.: 31 AF XY: 0.00000973 AC XY: 7 AN XY: 719276

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000136

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000677 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Color Diagnostics, LLC DBA Color Health	Sep 20, 2023	This missense variant replaces alanine with threonine at codon 1746 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 not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 1/229570 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	Oct 01, 2023	The p.A1739T variant (also known as c.5215G>A), located in coding exon 36 of the MYH11 gene, results from a G to A substitution at nucleotide position 5215. The alanine at codon 1739 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 10, 2022

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. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 465747). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1746 of the MYH11 protein (p.Ala1746Thr). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	.;.;.;D
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	.;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.19	T;T;.;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.066	.;.;.;B
Vest4		0.19
MutPred		0.41		.;.;Gain of phosphorylation at A1739 (P = 0.0339);Gain of phosphorylation at A1739 (P = 0.0339);
MVP		0.45
MPC		0.17
ClinPred		0.14	T
GERP RS		2.7
Varity_R		0.10
gMVP		0.068

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: rs1029371842; hg19: chr16-15812252;