NM_002474.3:c.4366-655A>G

Variant names:

• chr16-15722289-T-C
• rs2384933
• NM_002474.3:c.4366-655A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002474.3(MYH11):​c.4366-655A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 152,128 control chromosomes in the GnomAD database, including 42,740 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42740 hom., cov: 33)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.987
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

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.4366-655A>G		intron	N/A	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4387-655A>G		intron	N/A	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.948-1902T>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.4366-655A>G		intron	N/A	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4387-655A>G		intron	N/A	ENSP00000407821.2
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.948-1902T>C		intron	N/A	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112966 AN: 152012 Hom.: 42678 Cov.: 33

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.737

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.743 AC: 113087 AN: 152128 Hom.: 42740 Cov.: 33 AF XY: 0.745 AC XY: 55402 AN XY: 74352

African (AFR) AF: 0.898 AC: 37312 AN: 41528

American (AMR) AF: 0.722 AC: 11043 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.804 AC: 2787 AN: 3468

East Asian (EAS) AF: 0.696 AC: 3591 AN: 5162

South Asian (SAS) AF: 0.752 AC: 3621 AN: 4818

European-Finnish (FIN) AF: 0.696 AC: 7355 AN: 10566

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.661 AC: 44932 AN: 67978

Other (OTH) AF: 0.737 AC: 1560 AN: 2116

Alfa AF: 0.709 Hom.: 7287

Bravo AF: 0.751

Asia WGS AF: 0.716 AC: 2491 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.61
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs2384933; hg19: chr16-15816146;