rs16967510

chr16-15724985-A-Cchr16-15724985-A-G

Variant summary

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

The NM_002474.3(MYH11):c.3866T>G(p.Val1289Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,074 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. V1289A) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34

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]

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.3866T>G	p.Val1289Gly	missense_variant	29/41	ENST00000300036.6
MYH11	NM_001040113.2	c.3887T>G	p.Val1296Gly	missense_variant	30/43	ENST00000452625.7
NDE1	NM_017668.3	c.*734A>C		3_prime_UTR_variant	9/9	ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3866T>G	p.Val1289Gly	missense_variant	29/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3887T>G	p.Val1296Gly	missense_variant	30/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.*734A>C		3_prime_UTR_variant	9/9	1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251062 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135726

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

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	Benign	0.12
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D;D;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.026	D;D;.;D
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.46	.;.;.;P
Vest4		0.44
MutPred		0.46		.;.;Loss of stability (P = 0.008);Loss of stability (P = 0.008);
MVP		0.60
MPC		0.50
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs16967510; hg19: chr16-15818842;