NM_002474.3:c.3604G>A

Variant names:

• chr16-15732611-C-T
• rs112657320
• NM_002474.3:c.3604G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_002474.3(MYH11):​c.3604G>A​(p.Ala1202Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,240 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1202V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000082 (1 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009503961).
• BP6: Variant 16-15732611-C-T is Benign according to our data. Variant chr16-15732611-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000873 (133/152348) while in subpopulation AFR AF = 0.00301 (125/41582). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.3604G>A	p.Ala1202Thr	missense	Exon 27 of 41	NP_002465.1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.3625G>A	p.Ala1209Thr	missense	Exon 28 of 43	NP_001035202.1
	MYH11	NM_001040114.2		c.3625G>A	p.Ala1209Thr	missense	Exon 28 of 42	NP_001035203.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.3604G>A	p.Ala1202Thr	missense	Exon 27 of 41	ENSP00000300036.5
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.3625G>A	p.Ala1209Thr	missense	Exon 28 of 43	ENSP00000407821.2
	MYH11	ENST00000396324.7	TSL:1	c.3625G>A	p.Ala1209Thr	missense	Exon 28 of 42	ENSP00000379616.3

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152230 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251460 AF XY: 0.000140

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.0000756 AC XY: 55 AN XY: 727248

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

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

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

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152348 Hom.: 1 Cov.: 33 AF XY: 0.000872 AC XY: 65 AN XY: 74502

African (AFR) AF: 0.00301 AC: 125 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000490 Hom.: 1

Bravo AF: 0.000722

ESP6500AA AF: 0.00228 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	Aortic aneurysm, familial thoracic 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.62
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.74	N
PhyloP100		1.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.17
Sift	Benign	0.92	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.23
MPC		0.17
ClinPred		0.0041	T
GERP RS		3.9
Varity_R		0.029
gMVP		0.033
Mutation Taster		=98/2	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: rs112657320; hg19: chr16-15826468;