rs16967494

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002474.3(MYH11):​c.3700G>C​(p.Ala1234Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,564 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1234T) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.566

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]

(HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3700G>C	p.Ala1234Pro	missense_variant	28/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3721G>C	p.Ala1241Pro	missense_variant	29/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3721G>C	p.Ala1241Pro	missense_variant	29/42		NP_001035203.1
MYH11	NM_022844.3	c.3700G>C	p.Ala1234Pro	missense_variant	28/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3700G>C	p.Ala1234Pro	missense_variant	28/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.3721G>C	p.Ala1241Pro	missense_variant	29/43	1	NM_001040113.2	ENSP00000407821
	ENST00000574212.1	n.327+6C>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151564 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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.: 38

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151564 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 73958

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;.;.;D
Eigen	Benign	0.096
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.0	.;.;M;M
MutationTaster	Benign	0.0062	P;P;P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.099	T;T;.;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.68	.;.;.;P
Vest4		0.60
MutPred		0.48		.;.;Gain of catalytic residue at A1234 (P = 0.0312);Gain of catalytic residue at A1234 (P = 0.0312);
MVP		0.46
MPC		0.71
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.57
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs16967494; hg19: chr16-15820863;