NM_002474.3:c.3652-1889G>A

Variant names:

• chr16-15728943-C-T
• rs17284809
• NM_002474.3:c.3652-1889G>A

Variant summary

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

The NM_002474.3(MYH11):​c.3652-1889G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 151,936 control chromosomes in the GnomAD database, including 131 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 0.035 (131 hom., cov: 31)
• Consequence: MYH11 NM_002474.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 3 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

ENSG00000263335 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3652-1889G>A		intron_variant	Intron 27 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3673-1889G>A		intron_variant	Intron 28 of 42	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3673-1889G>A		intron_variant	Intron 28 of 41		NP_001035203.1
MYH11	NM_022844.3	c.3652-1889G>A		intron_variant	Intron 27 of 41		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3652-1889G>A		intron_variant	Intron 27 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3673-1889G>A		intron_variant	Intron 28 of 42	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5248 AN: 151838 Hom.: 131 Cov.: 31

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.0312

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

GnomAD4 genome AF: 0.0345 AC: 5248 AN: 151936 Hom.: 131 Cov.: 31 AF XY: 0.0318 AC XY: 2358 AN XY: 74260

African (AFR) AF: 0.0102 AC: 425 AN: 41470

American (AMR) AF: 0.0284 AC: 433 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5144

South Asian (SAS) AF: 0.0165 AC: 79 AN: 4800

European-Finnish (FIN) AF: 0.0369 AC: 390 AN: 10558

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0560 AC: 3807 AN: 67932

Other (OTH) AF: 0.0309 AC: 65 AN: 2106

Alfa AF: 0.0436 Hom.: 202

Bravo AF: 0.0329

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.1
DANN	Benign	0.60
PhyloP100		0.049
Mutation Taster		=100/0	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: rs17284809; hg19: chr16-15822800;