16-15726879-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002474.3(MYH11):c.3827C>G(p.Ala1276Gly) 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 benign outcome for this variant. 16/21 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. A1276V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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]

(HGNC:):

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.1541248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.3827C>G	p.Ala1276Gly	missense_variant	28/41	ENST00000300036.6
MYH11	NM_001040113.2	c.3848C>G	p.Ala1283Gly	missense_variant	29/43	ENST00000452625.7
MYH11	NM_001040114.2	c.3848C>G	p.Ala1283Gly	missense_variant	29/42
MYH11	NM_022844.3	c.3827C>G	p.Ala1276Gly	missense_variant	28/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3827C>G	p.Ala1276Gly	missense_variant	28/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3848C>G	p.Ala1283Gly	missense_variant	29/43	1	NM_001040113.2
	ENST00000574212.1	n.206G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Invitae

Jun 01, 2018

This sequence change replaces alanine with glycine at codon 1283 of the MYH11 protein (p.Ala1283Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH11-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.96
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	0.65	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.72	N;N;.;N
REVEL	Benign	0.15
Sift	Benign	0.30	T;T;.;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.29
MutPred		0.36		.;.;Loss of stability (P = 0.1305);Loss of stability (P = 0.1305);
MVP		0.52
MPC		0.20
ClinPred		0.25	T
GERP RS		2.7
Varity_R		0.065
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs547038802; hg19: chr16-15820736;