NM_002474.3:c.429G>C

Variant names:

• chr16-15823328-C-G
• NM_002474.3:c.429G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002474.3(MYH11):​c.429G>C​(p.Lys143Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K143K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.897

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.429G>C	p.Lys143Asn	missense_variant	Exon 3 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.429G>C	p.Lys143Asn	missense_variant	Exon 3 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.429G>C	p.Lys143Asn	missense_variant	Exon 3 of 42		NP_001035203.1
MYH11	NM_022844.3	c.429G>C	p.Lys143Asn	missense_variant	Exon 3 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.429G>C	p.Lys143Asn	missense_variant	Exon 3 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.429G>C	p.Lys143Asn	missense_variant	Exon 3 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.97	.;.;.;D
Vest4		0.65
MutPred		0.60		Loss of methylation at K143 (P = 0.0135);Loss of methylation at K143 (P = 0.0135);Loss of methylation at K143 (P = 0.0135);Loss of methylation at K143 (P = 0.0135);
MVP		0.84
MPC		1.9
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-15917185;