rs587781052

chr16-15727006-C-TchrNT_187607.1-1385016-C-Tchr16-15727006-C-GchrNT_187607.1-1385016-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002474.3(MYH11):c.3700G>A(p.Ala1234Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,080 control chromosomes in the GnomAD database, including 58,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3881 hom., cov: 30)

Exomes 𝑓: 0.27 ( 55083 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.566

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:

(HGNC:):

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYH11

BP4

Computational evidence support a benign effect (MetaRNN=0.0012848079).

BP6

Variant 16-15727006-C-T is Benign according to our data. Variant chr16-15727006-C-T is described in ClinVar as [Benign]. Clinvar id is 138334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15727006-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH11	NM_002474.3 linkuse as main transcript	c.3700G>A	p.Ala1234Thr	missense_variant	28/41	ENST00000300036.6
MYH11	NM_001040113.2 linkuse as main transcript	c.3721G>A	p.Ala1241Thr	missense_variant	29/43	ENST00000452625.7
MYH11	NM_001040114.2 linkuse as main transcript	c.3721G>A	p.Ala1241Thr	missense_variant	29/42
MYH11	NM_022844.3 linkuse as main transcript	c.3700G>A	p.Ala1234Thr	missense_variant	28/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.3700G>A	p.Ala1234Thr	missense_variant	28/41	1	NM_002474.3	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.3721G>A	p.Ala1241Thr	missense_variant	29/43	1	NM_001040113.2		P35749-3
	ENST00000574212.1 linkuse as main transcript	n.327+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32222

AN:

151472

Hom.:

3880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0876

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.250

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.206

GnomAD3 exomes

AF:

0.247

AC:

61945

AN:

251094

Hom.:

8206

AF XY:

0.246

AC XY:

33328

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.0828

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.296

Gnomad SAS exome

AF:

0.219

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.233

GnomAD4 exome

AF:

0.270

AC:

394158

AN:

1461488

Hom.:

55083

Cov.:

AF XY:

0.268

AC XY:

194872

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.0841

Gnomad4 AMR exome

AF:

0.253

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.333

Gnomad4 SAS exome

AF:

0.220

Gnomad4 FIN exome

AF:

0.258

Gnomad4 NFE exome

AF:

0.283

Gnomad4 OTH exome

AF:

0.245

GnomAD4 genome

AF:

0.213

AC:

32222

AN:

151592

Hom.:

3881

Cov.:

AF XY:

0.212

AC XY:

15705

AN XY:

74038

show subpopulations

Gnomad4 AFR

AF:

0.0876

Gnomad4 AMR

AF:

0.238

Gnomad4 ASJ

AF:

0.143

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.229

Gnomad4 FIN

AF:

0.250

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.207

Alfa

AF:

0.251

Hom.:

13209

Bravo

AF:

0.206

TwinsUK

AF:

0.272

AC:

1010

ALSPAC

AF:

0.290

AC:

1117

ESP6500AA

AF:

0.0988

AC:

434

ESP6500EA

AF:

0.262

AC:

2253

ExAC

AF:

0.246

AC:

29828

Asia WGS

AF:

0.275

AC:

956

AN:

3478

EpiCase

AF:

0.255

EpiControl

AF:

0.254

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 25, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ala1241Thr in exon 29 of MYH11: This variant is not expected to have clinical si gnificance because it has been identified in 26.2% (2253/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs16967494). -

Aortic aneurysm, familial thoracic 4

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Visceral myopathy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Lissencephaly, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

Cadd

Uncertain

Dann

Uncertain

0.98

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.90

D;D;D;D

MetaRNN

Benign

0.0013

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.021

P;P;P;P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.85

N;N;.;N

REVEL

Benign

0.25

Sift

Benign

0.26

T;T;.;T

Sift4G

Benign

0.32

T;T;T;T

Polyphen

0.013

.;.;.;B

Vest4

0.082

MPC

0.34

ClinPred

0.0066

GERP RS

4.7

Varity_R

0.096

gMVP

0.049

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