rs538137003

Positions:

• chr16-15719679-T-A
• chr16-15719679-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002474.3(MYH11):​c.4988A>T​(p.Asp1663Val) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4988A>T	p.Asp1663Val	missense_variant	35/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5009A>T	p.Asp1670Val	missense_variant	36/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-4512T>A		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4988A>T	p.Asp1663Val	missense_variant	35/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5009A>T	p.Asp1670Val	missense_variant	36/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-4512T>A		intron_variant		1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1670 of the MYH11 protein (p.Asp1670Val). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 534152). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.3	.;.;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.4	D;D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.78	.;.;.;P
Vest4		0.84
MutPred		0.51		.;.;Gain of MoRF binding (P = 0.0367);Gain of MoRF binding (P = 0.0367);
MVP		0.76
MPC		0.74
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.61

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: rs538137003; hg19: chr16-15813536;