16-15756433-G-C

Variant names:

• chr16-15756433-G-C
• rs1555562404
• NM_002474.3:c.1657C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002474.3(MYH11):​c.1657C>G​(p.Leu553Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L553L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30
• Publications: 0 publications found

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]

MYH11 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28593868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.1657C>G	p.Leu553Val	missense_variant	Exon 14 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.1678C>G	p.Leu560Val	missense_variant	Exon 15 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.1678C>G	p.Leu560Val	missense_variant	Exon 15 of 42		NP_001035203.1
MYH11	NM_022844.3	c.1657C>G	p.Leu553Val	missense_variant	Exon 14 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.1657C>G	p.Leu553Val	missense_variant	Exon 14 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.1678C>G	p.Leu560Val	missense_variant	Exon 15 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Feb 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1657C>G (p.L553V) alteration is located in exon 14 (coding exon 13) of the MYH11 gene. This alteration results from a C to G substitution at nucleotide position 1657, causing the leucine (L) at amino acid position 553 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.60	.;.;.;D
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0024
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	.;.;L;L
PhyloP100		2.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.91	N;N;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.30	T;T;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.0010	.;.;.;B
Vest4		0.29
MutPred		0.77		.;.;Gain of ubiquitination at K552 (P = 0.1235);Gain of ubiquitination at K552 (P = 0.1235);
MVP		0.80
MPC		0.79
ClinPred		0.51	D
GERP RS		4.4
Varity_R		0.14
gMVP		0.70
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555562404; hg19: chr16-15850290;