NM_002474.3:c.4089G>C

Variant names:

• chr16-15724674-C-G
• rs748585013
• NM_002474.3:c.4089G>C

Variant summary

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

The NM_002474.3(MYH11):​c.4089G>C​(p.Glu1363Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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 rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.4089G>C	p.Glu1363Asp	missense_variant	Exon 30 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4110G>C	p.Glu1370Asp	missense_variant	Exon 31 of 43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.*423C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.4089G>C	p.Glu1363Asp	missense_variant	Exon 30 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4110G>C	p.Glu1370Asp	missense_variant	Exon 31 of 43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.*423C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250962 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135688

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;.;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.6	.;.;M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Pathogenic	0.67
Sift	Benign	0.095	T;T;.;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.76	.;.;.;P
Vest4		0.65
MutPred		0.53		.;.;Loss of methylation at K1359 (P = 0.1376);Loss of methylation at K1359 (P = 0.1376);
MVP		0.89
MPC		0.68
ClinPred		0.74	D
GERP RS		1.8
Varity_R		0.30
gMVP		0.31

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: rs748585013; hg19: chr16-15818531;