rs148893135

chr16-15748152-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS1

The NM_002474.3(MYH11):c.2075C>T(p.Ala692Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,613,786 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A692A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 10.0

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP6: Variant 16-15748152-G-A is Benign according to our data. Variant chr16-15748152-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201054.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}. Variant chr16-15748152-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000624 (912/1461584) while in subpopulation NFE AF= 0.000779 (866/1112008). AF 95% confidence interval is 0.000735. There are 1 homozygotes in gnomad4_exome. There are 463 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.2075C>T	p.Ala692Val	missense_variant	17/41	ENST00000300036.6
MYH11	NM_001040113.2	c.2096C>T	p.Ala699Val	missense_variant	18/43	ENST00000452625.7
MYH11	NM_001040114.2	c.2096C>T	p.Ala699Val	missense_variant	18/42
MYH11	NM_022844.3	c.2075C>T	p.Ala692Val	missense_variant	17/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.2075C>T	p.Ala692Val	missense_variant	17/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.2096C>T	p.Ala699Val	missense_variant	18/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000255 AC: 64 AN: 250856 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135682

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000624 AC: 912 AN: 1461584 Hom.: 1 Cov.: 34 AF XY: 0.000637 AC XY: 463 AN XY: 727088

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000779

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74366

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000518 Hom.: 1

Bravo AF: 0.000310

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000981

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	Identified in a patient with severe arterial tortuosity and coarctation of the aorta, and in the asymptomatic mother (Loup et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23696586) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The MYH11 c.2075C>T; p.Ala692Val variant (rs148893135), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.002 % (69/ 282,246 alleles) in the Genome Aggregation Database. The alanine at codon 692 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Ala692Val variant is uncertain at this time. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 12, 2023	The p.A692V variant (also known as c.2075C>T), located in coding exon 16 of the MYH11 gene, results from a C to T substitution at nucleotide position 2075. The alanine at codon 692 is replaced by valine, an amino acid with similar properties. This alteration was reported in an infant with arterial tortuosity and the unaffected mother (Loup O et al. Circ Cardiovasc Imaging, 2013 May;6:487-90). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2023	This missense variant replaces alanine with valine at codon 699 of the MYH11 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an asymptomatic infant with severe arterial tortuosity and coarctation and in her unaffected mother (variant cited as MYH11 c.2075C>T, p.Ala692Val, using a different transcript, PMID: 23696586). This variant has been identified in 69/282246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aortic aneurysm, familial thoracic 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 699 of the MYH11 protein (p.Ala699Val). This variant is present in population databases (rs148893135, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 201054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 21, 2023

Variant summary: MYH11 c.2096C>T (p.Ala699Val) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 250856 control chromosomes, predominantly at a frequency of 0.00049 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 392 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2096C>T has been reported in the literature in an individual with a clinical phenotype that is not compatible with thoracic aortic aneurysm; her unaffected mother also carried the variant (Loup_2013). This report does 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.016	D;D;.;D
Sift4G	Uncertain	0.060	T;T;T;T
Polyphen		0.98	.;.;.;D
Vest4		0.59
MVP		0.79
MPC		1.6
ClinPred		0.69	D
GERP RS		4.9
Varity_R		0.38
gMVP		0.79

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: rs148893135; hg19: chr16-15842009;