rs587781051

chr16-15735562-C-TchrNT_187607.1-1393572-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002474.3(MYH11):c.3310G>A(p.Ala1104Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,614,140 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1104G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (32 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.26

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.0028044581).
• BP6: Variant 16-15735562-C-T is Benign according to our data. Variant chr16-15735562-C-T is described in ClinVar as [Benign]. Clinvar id is 138333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15735562-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1740/152268) while in subpopulation AFR AF= 0.0403 (1673/41544). AF 95% confidence interval is 0.0387. There are 34 homozygotes in gnomad4. There are 813 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.3310G>A	p.Ala1104Thr	missense_variant	26/41	ENST00000300036.6
MYH11	NM_001040113.2	c.3331G>A	p.Ala1111Thr	missense_variant	27/43	ENST00000452625.7
MYH11	NM_001040114.2	c.3331G>A	p.Ala1111Thr	missense_variant	27/42
MYH11	NM_022844.3	c.3310G>A	p.Ala1104Thr	missense_variant	26/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3310G>A	p.Ala1104Thr	missense_variant	26/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3331G>A	p.Ala1111Thr	missense_variant	27/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1739 AN: 152150 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.00294 AC: 739 AN: 251436 Hom.: 11 AF XY: 0.00210 AC XY: 285 AN XY: 135896

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00118 AC: 1729 AN: 1461872 Hom.: 32 Cov.: 33 AF XY: 0.000947 AC XY: 689 AN XY: 727240

Gnomad4 AFR exome AF: 0.0410

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000953

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.0114 AC: 1740 AN: 152268 Hom.: 34 Cov.: 32 AF XY: 0.0109 AC XY: 813 AN XY: 74450

Gnomad4 AFR AF: 0.0403

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00589 Hom.: 7

Bravo AF: 0.0129

ESP6500AA AF: 0.0394 AC: 173

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00385 AC: 468

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 15, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Aortic aneurysm, familial thoracic 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.94	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.087	T;T;.;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.0020	.;.;.;B
Vest4		0.18
MVP		0.53
MPC		0.17
ClinPred		0.0086	T
GERP RS		3.5
Varity_R		0.044
gMVP		0.13

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: rs34263860; hg19: chr16-15829419;