rs748529935
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_002474.3(MYH11):c.4598C>T(p.Ser1533Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1533C) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
MYH11
NM_002474.3 missense
NM_002474.3 missense
Scores
2
11
4
Clinical Significance
Conservation
PhyloP100: 6.82
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]
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, MYH11
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH11 | NM_002474.3 | c.4598C>T | p.Ser1533Phe | missense_variant | 33/41 | ENST00000300036.6 | |
MYH11 | NM_001040113.2 | c.4619C>T | p.Ser1540Phe | missense_variant | 34/43 | ENST00000452625.7 | |
NDE1 | NM_017668.3 | c.948-3159G>A | intron_variant | ENST00000396354.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH11 | ENST00000300036.6 | c.4598C>T | p.Ser1533Phe | missense_variant | 33/41 | 1 | NM_002474.3 | P3 | |
MYH11 | ENST00000452625.7 | c.4619C>T | p.Ser1540Phe | missense_variant | 34/43 | 1 | NM_001040113.2 | ||
NDE1 | ENST00000396354.6 | c.948-3159G>A | intron_variant | 1 | NM_017668.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251372Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727212
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces serine with phenylalanine at codon 1540 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 4/251372 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.015
.;.;.;B
Vest4
MutPred
0.49
.;.;Loss of phosphorylation at S1533 (P = 0.0182);Loss of phosphorylation at S1533 (P = 0.0182);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at