rs752441599

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_002474.3(MYH11):​c.70C>G​(p.Pro24Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MYH11
NM_002474.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.81
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH11NM_002474.3 linkc.70C>G p.Pro24Ala missense_variant Exon 2 of 41 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.70C>G p.Pro24Ala missense_variant Exon 2 of 43 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkc.70C>G p.Pro24Ala missense_variant Exon 2 of 42 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkc.70C>G p.Pro24Ala missense_variant Exon 2 of 42 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkc.70C>G p.Pro24Ala missense_variant Exon 2 of 41 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.70C>G p.Pro24Ala missense_variant Exon 2 of 43 1 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250132
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135318
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:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
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:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Dec 07, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 24 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 1/250132 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 22, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P24A variant (also known as c.70C>G), located in coding exon 1 of the MYH11 gene, results from a C to G substitution at nucleotide position 70. The proline at codon 24 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Aortic aneurysm, familial thoracic 4 Uncertain:1
Dec 25, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 24 of the MYH11 protein (p.Pro24Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 577468). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Uncertain:1
Sep 28, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
.;.;.;D
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Benign
0.034
D
MetaRNN
Uncertain
0.55
D;D;D;D
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
2.0
M;M;M;M
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-4.8
D;D;.;D
REVEL
Uncertain
0.45
Sift
Benign
0.10
T;T;.;T
Sift4G
Benign
0.20
T;T;T;T
Polyphen
0.0010
.;.;.;B
Vest4
0.66
MutPred
0.44
Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);Gain of MoRF binding (P = 0.0561);
MVP
0.80
MPC
0.78
ClinPred
0.94
D
GERP RS
5.8
Varity_R
0.28
gMVP
0.48

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.

Other links and lift over

dbSNP: rs752441599; hg19: chr16-15932040; API