rs138206921

Positions:

chr16-15715060-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong

The NM_002474.3(MYH11):c.5635G>A(p.Val1879Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.848

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 -11 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=0.024163097).

BP6

Variant 16-15715060-C-T is Benign according to our data. Variant chr16-15715060-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 418581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH11	NM_002474.3 linkuse as main transcript	c.5635G>A	p.Val1879Ile	missense_variant	40/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2 linkuse as main transcript	c.5656G>A	p.Val1886Ile	missense_variant	41/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3 linkuse as main transcript	c.948-9131C>T		intron_variant		ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.5635G>A	p.Val1879Ile	missense_variant	40/41	1	NM_002474.3	ENSP00000300036	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.5656G>A	p.Val1886Ile	missense_variant	41/43	1	NM_001040113.2	ENSP00000407821		P35749-3
NDE1	ENST00000396354.6 linkuse as main transcript	c.948-9131C>T		intron_variant		1	NM_017668.3	ENSP00000379642	P1	Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

250956

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00169

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1461228

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00191

Gnomad4 NFE exome

AF:

0.0000710

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000296

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00321

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2020	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 specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 15, 2023

Variant summary: MYH11 c.5656G>A (p.Val1886Ile) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250956 control chromosomes. The observed variant frequency is approximately 16-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05), strongly suggesting that the variant is benign. c.5656G>A has been reported in the literature in an individual affected with Thoracic Aortic Aneurysms without strong evidence of causality (Salmasi_2022). This report does not provide unequivocal conclusions about association of the variant with Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35830949). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Aortic aneurysm, familial thoracic 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2021

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Benign

0.84

DEOGEN2

Benign

0.28

.;.;.;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.1

.;.;L;L

MutationTaster

Benign

0.72

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

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.14

N;N;.;N

REVEL

Benign

0.21

Sift

Benign

0.38

T;T;.;T

Sift4G

Benign

0.51

T;T;T;T

Polyphen

0.033

.;.;.;B

Vest4

0.38

MVP

0.35

MPC

0.18

ClinPred

0.096

GERP RS

4.6

Varity_R

0.058

gMVP

0.089

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