rs111854563

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_002474.3(MYH11):c.4673C>T(p.Thr1558Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,613,960 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1558T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 3 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 10.0

Variant links:

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]

MYH11 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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=0.10667306).

BP6

Variant 16-15720957-G-A is Benign according to our data. Variant chr16-15720957-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180419.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=1}. Variant chr16-15720957-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000736 (112/152074) while in subpopulation NFE AF= 0.00118 (80/67990). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH11	NM_002474.3 linkuse as main transcript	c.4673C>T	p.Thr1558Met	missense_variant	33/41	ENST00000300036.6
MYH11	NM_001040113.2 linkuse as main transcript	c.4694C>T	p.Thr1565Met	missense_variant	34/43	ENST00000452625.7
NDE1	NM_017668.3 linkuse as main transcript	c.948-3234G>A		intron_variant		ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.4673C>T	p.Thr1558Met	missense_variant	33/41	1	NM_002474.3	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.4694C>T	p.Thr1565Met	missense_variant	34/43	1	NM_001040113.2		P35749-3
NDE1	ENST00000396354.6 linkuse as main transcript	c.948-3234G>A		intron_variant		1	NM_017668.3	P1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.000737

AC:

112

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000680

AC:

171

AN:

251482

Hom.:

AF XY:

0.000721

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000859

AC:

1256

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

635

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152074

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000931

Hom.:

Bravo

AF:

0.000502

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Nov 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 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. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	This variant is associated with the following publications: (PMID: 23142374, 26017485, 27647783) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2016	Variant summary: This c.4694C>T variant affects a conserved nucleotide, resulting in amino acid change from Thr to Met. 3/4 in-silico tools predict this variant to be damaging; however they are not definite. This variant was found in 94/122406 control chromosomes at a frequency of 0.0007679, which is more than 613 times greater than the maximal expected frequency of a pathogenic allele (0.0000013) in this gene, suggesting this variant is benign. At least one clinical lab has classified this variant as likely benign. Taken together, this variant has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYH11: PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2023	- -

Aortic aneurysm, familial thoracic 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 14, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Isolated thoracic aortic aneurysm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Department of Vascular Biology, Beijing Anzhen Hospital

Sep 01, 2018

- -

MYH11-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

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

Benign

0.18

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

.;.;.;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.2

.;.;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.4

D;D;.;D

REVEL

Uncertain

0.54

Sift

Benign

0.081

T;T;.;T

Sift4G

Benign

0.070

T;T;T;T

Polyphen

0.99

.;.;.;D

Vest4

0.41

MVP

0.74

MPC

0.63

ClinPred

0.18

GERP RS

5.0

Varity_R

0.16

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over