rs16967494

Variant names:

• chr16-15727006-C-T
• rs16967494
• NM_002474.3:c.3700G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-15727006-C-T
• chr16-15727006-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002474.3(MYH11):​c.3700G>A​(p.Ala1234Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,080 control chromosomes in the GnomAD database, including 58,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3881 hom., cov: 30)
  • Exomes 𝑓: 0.27 (55083 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.566
• Publications: 61 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012848079).
• BP6: Variant 16-15727006-C-T is Benign according to our data. Variant chr16-15727006-C-T is described in ClinVar as Benign. ClinVar VariationId is 138334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_002474.3	MANE Select	c.3700G>A	p.Ala1234Thr	missense	Exon 28 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.3721G>A	p.Ala1241Thr	missense	Exon 29 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.3721G>A	p.Ala1241Thr	missense	Exon 29 of 42	NP_001035203.1	P35749-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.3700G>A	p.Ala1234Thr	missense	Exon 28 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.3721G>A	p.Ala1241Thr	missense	Exon 29 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.3721G>A	p.Ala1241Thr	missense	Exon 29 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32222 AN: 151472 Hom.: 3880 Cov.: 30

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.206

GnomAD2 exomes AF: 0.247 AC: 61945 AN: 251094 AF XY: 0.246

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.270 AC: 394158 AN: 1461488 Hom.: 55083 Cov.: 38 AF XY: 0.268 AC XY: 194872 AN XY: 727068

African (AFR) AF: 0.0841 AC: 2814 AN: 33480

American (AMR) AF: 0.253 AC: 11305 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3722 AN: 26136

East Asian (EAS) AF: 0.333 AC: 13234 AN: 39700

South Asian (SAS) AF: 0.220 AC: 18983 AN: 86258

European-Finnish (FIN) AF: 0.258 AC: 13693 AN: 53044

Middle Eastern (MID) AF: 0.130 AC: 752 AN: 5768

European-Non Finnish (NFE) AF: 0.283 AC: 314851 AN: 1111986

Other (OTH) AF: 0.245 AC: 14804 AN: 60392

GnomAD4 genome AF: 0.213 AC: 32222 AN: 151592 Hom.: 3881 Cov.: 30 AF XY: 0.212 AC XY: 15705 AN XY: 74038

African (AFR) AF: 0.0876 AC: 3623 AN: 41366

American (AMR) AF: 0.238 AC: 3621 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1521 AN: 5102

South Asian (SAS) AF: 0.229 AC: 1097 AN: 4792

European-Finnish (FIN) AF: 0.250 AC: 2622 AN: 10498

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18669 AN: 67872

Other (OTH) AF: 0.207 AC: 434 AN: 2100

Alfa AF: 0.251 Hom.: 25161

Bravo AF: 0.206

TwinsUK AF: 0.272 AC: 1010

ALSPAC AF: 0.290 AC: 1117

ESP6500AA AF: 0.0988 AC: 434

ESP6500EA AF: 0.262 AC: 2253

ExAC AF: 0.246 AC: 29828

Asia WGS AF: 0.275 AC: 956 AN: 3478

EpiCase AF: 0.255

EpiControl AF: 0.254

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	3	Aortic aneurysm, familial thoracic 4 (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lissencephaly, Recessive (1)
-	-	1	Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (1)
-	-	1	Visceral myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.57
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.25
Sift	Benign	0.26	T
Sift4G	Benign	0.32	T
Polyphen		0.013	B
Vest4		0.082
MPC		0.34
ClinPred		0.0066	T
GERP RS		4.7
Varity_R		0.096
gMVP		0.049
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: rs16967494; hg19: chr16-15820863; COSMIC: COSV55543853; COSMIC: COSV55543853;