16-15720883-G-A

Variant names:

• chr16-15720883-G-A
• rs777170587
• NM_002474.3:c.4747C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BS1_Supporting

The NM_002474.3(MYH11):​c.4747C>T​(p.Arg1583Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1583Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.32
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000329 (5/151996) while in subpopulation AMR AF = 0.000197 (3/15242). AF 95% confidence interval is 0.000053. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.4747C>T	p.Arg1583Trp	missense	Exon 33 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.4768C>T	p.Arg1590Trp	missense	Exon 34 of 43	NP_001035202.1
	NDE1	NM_017668.3	MANE Select	c.948-3308G>A		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.4747C>T	p.Arg1583Trp	missense	Exon 33 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.4768C>T	p.Arg1590Trp	missense	Exon 34 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.4768C>T	p.Arg1590Trp	missense	Exon 34 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251414 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727206

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1112012

Other (OTH) AF: 0.0000828 AC: 5 AN: 60384

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74230

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.000197 AC: 3 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial thoracic aortic aneurysm and aortic dissection (3)
-	3	-	not provided (3)
-	2	-	Aortic aneurysm, familial thoracic 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.61		Gain of catalytic residue at A1582 (P = 0.1294)
MVP		0.75
MPC		0.73
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.73
gMVP		0.63
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs777170587; hg19: chr16-15814740;