rs369751362

Variant names:

• chr16-15720895-C-G
• NM_002474.3:c.4735G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-15720895-C-G
• chr16-15720895-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002474.3(MYH11):​c.4735G>C​(p.Asp1579His) 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: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4735G>C	p.Asp1579His	missense_variant	Exon 33 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4756G>C	p.Asp1586His	missense_variant	Exon 34 of 43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-3296C>G		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4735G>C	p.Asp1579His	missense_variant	Exon 33 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4756G>C	p.Asp1586His	missense_variant	Exon 34 of 43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-3296C>G		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jun 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;.;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.2	.;.;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D;D;.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.054	T;D;T;D
Polyphen		1.0	.;.;.;D
Vest4		0.65
MutPred		0.51		.;.;Gain of MoRF binding (P = 0.0405);Gain of MoRF binding (P = 0.0405);
MVP		0.78
MPC		0.75
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.72
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-15814752;