rs149241435

Positions:

• chr16-15726940-T-G

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.3766A>C​(p.Lys1256Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,613,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 6.26

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]

(HGNC:):

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.138589).
• BP6: Variant 16-15726940-T-G is Benign according to our data. Variant chr16-15726940-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263518.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000199 (291/1461146) while in subpopulation SAS AF= 0.000557 (48/86250). AF 95% confidence interval is 0.000431. There are 1 homozygotes in gnomad4_exome. There are 158 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.3766A>C	p.Lys1256Gln	missense_variant	28/41	ENST00000300036.6
MYH11	NM_001040113.2	c.3787A>C	p.Lys1263Gln	missense_variant	29/43	ENST00000452625.7
MYH11	NM_001040114.2	c.3787A>C	p.Lys1263Gln	missense_variant	29/42
MYH11	NM_022844.3	c.3766A>C	p.Lys1256Gln	missense_variant	28/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3766A>C	p.Lys1256Gln	missense_variant	28/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3787A>C	p.Lys1263Gln	missense_variant	29/43	1	NM_001040113.2
	ENST00000574212.1	n.267T>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151890 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000299 AC: 75 AN: 250990 Hom.: 1 AF XY: 0.000383 AC XY: 52 AN XY: 135724

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000199 AC: 291 AN: 1461146 Hom.: 1 Cov.: 30 AF XY: 0.000217 AC XY: 158 AN XY: 726878

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152008 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74308

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2019	The p.Lys1263Gln variant in MYH11 has been previously reported, but has been identified in 0.03% (39/129118) of European chromosomes in gnomAD, including 1 homozygous South Asian individual. It has been reported in ClinVar (ID 263518). Computational tools predict predict a impact to the protein, though this information is not predictive enough to determine pathogenicity. In summary, although the frequency of this variant suggests that it is benign, additional information is needed to determine its clinical significance. ACMG/AMP criteria applied: PP3 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2020	Has been previously reported as a variant of uncertain significance in 2 individuals with TAAD in the published literature (Weerakkody et al., 2018).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 263518; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29543232) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2022	The MYH11 c.3766A>C; p.Lys1256Gln variant (rs149241435), is reported in the literature in several individuals affected with thoracic aortic aneurysm and dissection (Chen 2021, Weerakkody 2018). However, this variant was reported in two probands with pathogenic variants in FBN1 and the MYH11 variant did not segregate within the two probands’ families, though specific clinical and inheritance information were not provided (Li 2021). This variant is reported in ClinVar (Variation ID: 263518) and is found in the South Asian population with an allele frequency of 0.0751% (23/30,616 alleles, including one homozygote) in the Genome Aggregation Database. The lysine at codon 1256 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.532). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of the p.Lys1256Gln variant is uncertain at this time. References: Chen ZR et al. Genetic variants in Chinese patients with sporadic Stanford type A aortic dissection. J Thorac Dis. 2021 Jul;13(7):4008-4022. PMID: 34422331. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232. -

Aortic aneurysm, familial thoracic 4 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 27, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This missense variant replaces lysine with glutamine at codon 1263 of the MYH11 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with thoracic aortic aneurysm and dissection (PMID: 29543232, 34422331, 34498425). Two of these individuals also carried a pathogenic variant in the FBN1 gene that could explain the observed phenotype (PMID: 34498425). This variant has also been reported in one individual affected with ischemic stroke, but was also present in multiple healthy control individuals (PMID: 36973604). This variant has been identified in 81/282316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 12, 2016	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2013

There is insufficient or conflicting evidence for classification of this alteration. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	0.053	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.89	N;N;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.86	T;T;.;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.98	.;.;.;D
Vest4		0.56
MVP		0.77
MPC		0.74
ClinPred		0.049	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.20

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: rs149241435; hg19: chr16-15820797;