chr16-15737617-C-A

Position:

• chr16-15737617-C-A

Variant summary

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

The NM_002474.3(MYH11):​c.3125G>T​(p.Arg1042Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,916 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.

• 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: 6.17

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, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3125G>T	p.Arg1042Leu	missense_variant	25/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3146G>T	p.Arg1049Leu	missense_variant	26/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3146G>T	p.Arg1049Leu	missense_variant	26/42		NP_001035203.1
MYH11	NM_022844.3	c.3125G>T	p.Arg1042Leu	missense_variant	25/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3125G>T	p.Arg1042Leu	missense_variant	25/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3146G>T	p.Arg1049Leu	missense_variant	26/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459916 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726330

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.6	.;.;M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.0	D;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.98	.;.;.;D
Vest4		0.81
MutPred		0.28		.;.;Loss of MoRF binding (P = 0.0183);Loss of MoRF binding (P = 0.0183);
MVP		0.91
MPC		0.80
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.75
gMVP		0.56

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: rs771297865; hg19: chr16-15831474;