rs375903462
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_003276.2(TMPO):c.718G>A(p.Ala240Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
TMPO
NM_003276.2 missense
NM_003276.2 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 4.47
Genes affected
TMPO (HGNC:11875): (thymopoietin) Through alternative splicing, this gene encodes several distinct LEM domain containing protein isoforms. LEM domain proteins include inner nuclear membrane and intranuclear proteins, and are involved in a variety of cellular functions including gene expression, chromatin organization, and replication and cell cycle control. The encoded alpha isoform is broadly diffuse in the nucleus and contains a lamin binding domain, while the beta and gamma isoforms are localized to the nuclear membrane and contain an HDAC3 interaction domain. The distinct isoforms may compete with each other when acting to chaperone other proteins and regulate transcription. [provided by RefSeq, Aug 2019]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2967739).
BS2
High AC in GnomAdExome4 at 33 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMPO | NM_001032283.3 | c.565+1137G>A | intron_variant | Intron 3 of 8 | ENST00000556029.6 | NP_001027454.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251348Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135854
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727234
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 10, 2014 | The Ala240Thr variant in TMPO has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 1/8600 of European American chromo somes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs375903462). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Ala240Thr variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 25, 2024 | The p.A240T variant (also known as c.718G>A), located in coding exon 4 of the TMPO gene, results from a G to A substitution at nucleotide position 718. The alanine at codon 240 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Loeys-Dietz syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 240 of the TMPO protein (p.Ala240Thr). This variant is present in population databases (rs375903462, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 36672271). ClinVar contains an entry for this variant (Variation ID: 179035). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMPO protein function. Experimental studies have shown that this missense change affects TMPO function (PMID: 36672271). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Functional studies in HEK293 cells suggest that p.(A240T) is not a disease-causing (PMID: 36672271); In silico analysis indicates that this missense variant does not alter protein structure/function; Has been reported as a maternally inherited variant in two males with dilated cardiomyopathy (PMID: 36672271); of note their mother was asymptomatic; This variant is associated with the following publications: (PMID: 36672271) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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