16-15718339-G-C

Variant names:

• chr16-15718339-G-C
• rs146043349
• NM_002474.3:c.5271C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002474.3(MYH11):​c.5271C>G​(p.Asp1757Glu) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1757N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 0 publications found

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]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21644413).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.5271C>G	p.Asp1757Glu	missense	Exon 37 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5292C>G	p.Asp1764Glu	missense	Exon 38 of 43	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.948-5852G>C		intron	N/A	NP_060138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5271C>G	p.Asp1757Glu	missense	Exon 37 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5292C>G	p.Asp1764Glu	missense	Exon 38 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.5292C>G	p.Asp1764Glu	missense	Exon 38 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.72	N
PhyloP100		0.025
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Benign	0.39	T
Sift4G	Benign	1.0	T
Polyphen		0.092	B
Vest4		0.30
MutPred		0.46		Loss of MoRF binding (P = 0.0789)
MVP		0.53
MPC		0.18
ClinPred		0.42	T
GERP RS		-1.1
Varity_R		0.054
gMVP		0.14
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs146043349; hg19: chr16-15812196;