rs16967494

chr16-15727006-C-Gchr16-15727006-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 where missense usually causes diseases, MYH11

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3700G>C	p.Ala1234Pro	missense_variant	28/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3721G>C	p.Ala1241Pro	missense_variant	29/43	1	NM_001040113.2
	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
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
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;