rs1176411300

Positions:

• chr16-15714973-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002474.3(MYH11):​c.5722G>A​(p.Asp1908Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5722G>A	p.Asp1908Asn	missense_variant	40/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5743G>A	p.Asp1915Asn	missense_variant	41/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-9218C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5722G>A	p.Asp1908Asn	missense_variant	40/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5743G>A	p.Asp1915Asn	missense_variant	41/43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-9218C>T		intron_variant		1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251138 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;.;.;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.3	.;.;M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D;D;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.053	T;T;.;T
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.078	.;.;.;B
Vest4		0.42
MutPred		0.50		.;.;Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);
MVP		0.82
MPC		0.20
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.36
gMVP		0.46

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: rs1176411300; hg19: chr16-15808830;