rs149241435

Variant names:

• chr16-15726940-T-G
• rs149241435
• NM_002474.3:c.3766A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1256L) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 6.26
• Publications: 10 publications found

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]

ENSG00000263335 (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]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• 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 VariationId is 263518.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000151 (23/152008) while in subpopulation SAS AF = 0.000417 (2/4798). AF 95% confidence interval is 0.000124. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3766A>C	p.Lys1256Gln	missense_variant	Exon 28 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3787A>C	p.Lys1263Gln	missense_variant	Exon 29 of 43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2	c.3787A>C	p.Lys1263Gln	missense_variant	Exon 29 of 42		NP_001035203.1
MYH11	NM_022844.3	c.3766A>C	p.Lys1256Gln	missense_variant	Exon 28 of 42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3766A>C	p.Lys1256Gln	missense_variant	Exon 28 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.3787A>C	p.Lys1263Gln	missense_variant	Exon 29 of 43	1	NM_001040113.2	ENSP00000407821.2

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

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 250990 AF XY: 0.000383

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 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

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000291 AC: 13 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86250

European-Finnish (FIN) AF: 0.000133 AC: 7 AN: 52786

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000176 AC: 196 AN: 1111918

Other (OTH) AF: 0.000199 AC: 12 AN: 60392

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

African (AFR) AF: 0.0000964 AC: 4 AN: 41482

American (AMR) AF: 0.000131 AC: 2 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4798

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000198 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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Oct 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 19, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jul 12, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1256Q variant (also known as c.3766A>C), located in coding exon 27 of the MYH11 gene, results from an A to C substitution at nucleotide position 3766. The lysine at codon 1256 is replaced by glutamine, an amino acid with similar properties. This variant has been detected in individuals with thoracic aortic aneurysm and dissection (TAAD) and in TAAD cohorts; however, clinical details were limited and co-occurring variants in other TAAD-related genes were also detected in some cases (Weerakkody R et al. Genet Med, 2018 Nov;20:1414-1422; Li J et al. Mol Genet Genomic Med. 2021 Oct;9(10):e1800; Chen ZR et al. J Thorac Dis, 2021 Jul;13:4008-4022). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Nov 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Benign:1

May 16, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH11 c.3787A>C (p.Lys1263Gln) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0003 in 250990 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 240 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06). c.3787A>C has been observed in individual(s) affected with Aortopathy without strong evidence for causality (Weerakkody_2018, Antonutti_2021, Chen_2021, Li_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: 33190788, 34422331, 37288276, 34498425, 29543232). ClinVar contains an entry for this variant (Variation ID: 263518). 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	Benign	0.31
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;.;.;T
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
MutationAssessor	Benign	1.6	.;.;L;L
PhyloP100		6.3
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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs149241435; hg19: chr16-15820797; COSMIC: COSV107354062; COSMIC: COSV107354062;