rs1409752157

Positions:

chr16-15735478-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_002474.3(MYH11):c.3394G>A(p.Ala1132Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.22495356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH11	NM_002474.3 linkuse as main transcript	c.3394G>A	p.Ala1132Thr	missense_variant	26/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2 linkuse as main transcript	c.3415G>A	p.Ala1139Thr	missense_variant	27/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_001040114.2 linkuse as main transcript	c.3415G>A	p.Ala1139Thr	missense_variant	27/42		NP_001035203.1
MYH11	NM_022844.3 linkuse as main transcript	c.3394G>A	p.Ala1132Thr	missense_variant	26/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6 linkuse as main transcript	c.3394G>A	p.Ala1132Thr	missense_variant	26/41	1	NM_002474.3	ENSP00000300036	P3	P35749-1
MYH11	ENST00000452625.7 linkuse as main transcript	c.3415G>A	p.Ala1139Thr	missense_variant	27/43	1	NM_001040113.2	ENSP00000407821		P35749-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2021

This sequence change replaces alanine with threonine at codon 1139 of the MYH11 protein (p.Ala1139Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of MYH11-related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;.;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.0054

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.6

.;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;N;.;N

REVEL

Benign

0.21

Sift

Benign

0.086

T;T;.;T

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.013

.;.;.;B

Vest4

0.26

MutPred

0.48

.;.;Gain of phosphorylation at A1132 (P = 0.0102);Gain of phosphorylation at A1132 (P = 0.0102);

MVP

0.66

MPC

0.19

ClinPred

0.57

GERP RS

4.5

Varity_R

0.086

gMVP

0.18

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