rs113964173

chr16-15715019-C-Gchr16-15715019-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.5676G>C(p.Glu1892Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 1,613,984 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1892K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (35 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.62

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]

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.013423175).
• BP6: Variant 16-15715019-C-G is Benign according to our data. Variant chr16-15715019-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 138358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15715019-C-G is described in Lovd as [Benign]. Variant chr16-15715019-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.005 (761/152312) while in subpopulation AMR AF= 0.00791 (121/15306). AF 95% confidence interval is 0.00676. There are 4 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.5676G>C	p.Glu1892Asp	missense_variant	40/41	ENST00000300036.6
MYH11	NM_001040113.2	c.5697G>C	p.Glu1899Asp	missense_variant	41/43	ENST00000452625.7
NDE1	NM_017668.3	c.948-9172C>G		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.5676G>C	p.Glu1892Asp	missense_variant	40/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.5697G>C	p.Glu1899Asp	missense_variant	41/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.948-9172C>G		intron_variant		1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152194 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00507 AC: 1273 AN: 251278 Hom.: 6 AF XY: 0.00536 AC XY: 728 AN XY: 135836

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00659

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00576

Gnomad NFE exome AF: 0.00612

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00569 AC: 8321 AN: 1461672 Hom.: 35 Cov.: 31 AF XY: 0.00570 AC XY: 4148 AN XY: 727158

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.00607

Gnomad4 OTH exome AF: 0.00677

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74474

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00604 Hom.: 2

Bravo AF: 0.00533

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00513 AC: 623

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 11, 2015	p.Glu1899Asp in exon 41 of MYH11: This variant is not expected to have clinical significance because it has been identified in 0.5% (623/121214) of pan ethnic c hromosomes including 3 homozygous individuals by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org/; dbSNP rs113964173). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYH11: BS1, BS2; NDE1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.037	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.88	.;.;.;P
Vest4		0.66
MutPred		0.39		.;.;Gain of MoRF binding (P = 0.092);Gain of MoRF binding (P = 0.092);
MVP		0.84
MPC		0.68
ClinPred		0.038	T
GERP RS		1.1
Varity_R		0.68
gMVP		0.33

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: rs113964173; hg19: chr16-15808876; COSMIC: COSV100260597; COSMIC: COSV100260597;