rs144244239

Positions:

• chr16-15757900-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_002474.3(MYH11):​c.1502G>A​(p.Arg501His) variant causes a missense change. The variant allele was found at a frequency of 0.000322 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R501R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 6.02

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19312811).
• BP6: Variant 16-15757900-C-T is Benign according to our data. Variant chr16-15757900-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201108.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=1}. Variant chr16-15757900-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000302 (46/152318) while in subpopulation EAS AF= 0.00135 (7/5176). AF 95% confidence interval is 0.000634. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.1502G>A	p.Arg501His	missense_variant	13/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.1523G>A	p.Arg508His	missense_variant	14/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.1523G>A	p.Arg508His	missense_variant	14/42		NP_001035203.1
MYH11	NM_022844.3	c.1502G>A	p.Arg501His	missense_variant	13/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.1502G>A	p.Arg501His	missense_variant	13/41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.1523G>A	p.Arg508His	missense_variant	14/43	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251476 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 223 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152318 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000359 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2020	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2019	This missense variant replaces arginine with histidine at codon 508 of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 63/282888 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and is fairly common in the East Asian population (22/19954 chromosomes; 0.11%). This variant allele frequency is greater than expected for the MYH11-related disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 26, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2023	Variant summary: MYH11 c.1523G>A (p.Arg508His) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251476 control chromosomes (gnomAD). The observed variant frequency is approximately 165 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. The variant, c.1523G>A, has been reported in the literature in individuals affected with Aortopathy (Fang_2017, vandeLuijtgaarden_2015) and suspected of thoracic artery aneurysm and dissection (Bharadwaj_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35372177, 28855619, 26017485). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and benign/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 30, 2019	- -

Aortic aneurysm, familial thoracic 4 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 03, 2018	The MYH11 c.1502G>A; p.Arg501His variant (rs144244239) is reported in the medical literature in at least two individuals with abdominal aortic aneurysm (Fang 2017, van de Luijtgaarden 2015). The variant is reported as uncertain by one source and likely benign by two sources, but with insufficient evidence to independently analyze (Variation ID: 201108). This variant is found in the general population with an overall allele frequency of 0.02% (59/277254 alleles) in the Genome Aggregation Database. The arginine at codon 501 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict this variant is deleterious. Considering available information, this variant is classified as uncertain. Pathogenic MYH11 variants are inherited in an autosomal dominant manner, and are associated with familial thoracic aortic aneurysm 4 (MIM: 132900). References: Fang M et al. Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. Sci Rep. 2017 Aug 30;7(1):10035. van de Luijtgaarden et al. First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. Hum Genet. 2015 Aug;134(8):881-93. -

MYH11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.1	.;.;M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.3	D;D;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.64
MVP		0.76
MPC		1.7
ClinPred		0.77	D
GERP RS		4.9
Varity_R		0.62
gMVP		0.63

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: rs144244239; hg19: chr16-15851757;