rs144421849

Positions:

• chr16-15718384-C-G
• chr16-15718384-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_002474.3(MYH11):​c.5226G>C​(p.Glu1742Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,604,814 control chromosomes in the GnomAD database, including 8 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 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (8 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 1.28

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 -12 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=0.016863614).
• BP6: Variant 16-15718384-C-G is Benign according to our data. Variant chr16-15718384-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 318101.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2}. Variant chr16-15718384-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000184 (28/152306) while in subpopulation SAS AF= 0.00352 (17/4828). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5226G>C	p.Glu1742Asp	missense_variant	37/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5247G>C	p.Glu1749Asp	missense_variant	38/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-5807C>G		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5226G>C	p.Glu1742Asp	missense_variant	37/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.5247G>C	p.Glu1749Asp	missense_variant	38/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.948-5807C>G		intron_variant		1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000583 AC: 140 AN: 240166 Hom.: 3 AF XY: 0.000623 AC XY: 81 AN XY: 130110

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000333 AC: 484 AN: 1452508 Hom.: 8 Cov.: 31 AF XY: 0.000400 AC XY: 289 AN XY: 722446

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00308

Gnomad4 FIN exome AF: 0.0000416

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000515

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74466

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000671 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYH11: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2019	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 05, 2018	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. -

Aortic aneurysm, familial thoracic 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -

Lissencephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 21, 2023

- -

MYH11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;.;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.8	.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.97	.;.;.;D
Vest4		0.62
MutPred		0.47		.;.;Loss of MoRF binding (P = 0.2075);Loss of MoRF binding (P = 0.2075);
MVP		0.80
MPC		0.68
ClinPred		0.10	T
GERP RS		3.7
Varity_R		0.62
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144421849; hg19: chr16-15812241;