rs774646317

Variant names:

• chr16-15771635-C-T
• rs774646317
• NM_002474.3:c.967G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002474.3(MYH11):​c.967G>A​(p.Asp323Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.43

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20273426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.967G>A	p.Asp323Asn	missense_variant	Exon 9 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.988G>A	p.Asp330Asn	missense_variant	Exon 10 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.988G>A	p.Asp330Asn	missense_variant	Exon 10 of 42		NP_001035203.1
MYH11	NM_022844.3	c.967G>A	p.Asp323Asn	missense_variant	Exon 9 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.967G>A	p.Asp323Asn	missense_variant	Exon 9 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.988G>A	p.Asp330Asn	missense_variant	Exon 10 of 43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Apr 27, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4 Uncertain:1

May 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been reported in an individual affected with an aortic aneurysm (PMID: 28074631). This variant is present in population databases (rs774646317, ExAC 0.003%). This sequence change replaces aspartic acid with asparagine at codon 330 of the MYH11 protein (p.Asp330Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.20	.;.;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.33	N;N;.;N
REVEL	Benign	0.27
Sift	Benign	0.37	T;T;.;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.28
MutPred		0.39		.;.;Loss of disorder (P = 0.14);Loss of disorder (P = 0.14);
MVP		0.61
MPC		0.75
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.51

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: rs774646317; hg19: chr16-15865492;