16-15718395-C-T

Variant names:

• chr16-15718395-C-T
• rs1029371842
• NM_002474.3:c.5215G>A
• MYH11 p.Ala1739Thr

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_002474.3(MYH11):​c.5215G>A​(p.Ala1739Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,446,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1739P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.361
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09647423).
• BP6: Variant 16-15718395-C-T is Benign according to our data. Variant chr16-15718395-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465747.

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.5215G>A	p.Ala1739Thr	missense	Exon 37 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5236G>A	p.Ala1746Thr	missense	Exon 38 of 43	NP_001035202.1	P35749-3
	NDE1	NM_017668.3	MANE Select	c.948-5796C>T		intron	N/A	NP_060138.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5215G>A	p.Ala1739Thr	missense	Exon 37 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5236G>A	p.Ala1746Thr	missense	Exon 38 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.5236G>A	p.Ala1746Thr	missense	Exon 38 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000436 AC: 1 AN: 229570 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000972

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1446676 Hom.: 0 Cov.: 31 AF XY: 0.00000973 AC XY: 7 AN XY: 719276

African (AFR) AF: 0.0000599 AC: 2 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5340

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1106592

Other (OTH) AF: 0.00 AC: 0 AN: 59860

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000677 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.36
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.19	T
Sift4G	Benign	0.34	T
Varity_R		0.10
gMVP		0.068
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1029371842;

hg19: chr16-15812252;