16-15726885-G-C

Variant names:

• chr16-15726885-G-C
• rs1060500723
• NM_002474.3:c.3821C>G
• MYH11 p.Ala1274Gly

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS1

The NM_002474.3(MYH11):​c.3821C>G​(p.Ala1274Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1274V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• 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, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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)

ENSG00000263335 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1803635).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000132 (2/152082) while in subpopulation EAS AF = 0.00039 (2/5126). AF 95% confidence interval is 0.000069. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.3821C>G	p.Ala1274Gly	missense	Exon 28 of 41	NP_002465.1	P35749-1
	MYH11	NM_001040113.2	MANE Plus Clinical	c.3842C>G	p.Ala1281Gly	missense	Exon 29 of 43	NP_001035202.1	P35749-3
	MYH11	NM_001040114.2		c.3842C>G	p.Ala1281Gly	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.3821C>G	p.Ala1274Gly	missense	Exon 28 of 41	ENSP00000300036.5	P35749-1
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.3842C>G	p.Ala1281Gly	missense	Exon 29 of 43	ENSP00000407821.2	P35749-3
	MYH11	ENST00000396324.7	TSL:1	c.3842C>G	p.Ala1281Gly	missense	Exon 29 of 42	ENSP00000379616.3	P35749-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151964 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic aneurysm, familial thoracic 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.34	T
Sift4G	Benign	0.37	T
Varity_R		0.083
gMVP		0.096
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060500723;

hg19: chr16-15820742;