rs754951098

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000266732.8(TMPO):ā€‹c.1030A>Gā€‹(p.Arg344Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,944 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 Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 33)
Exomes š‘“: 0.000065 ( 0 hom. )

Consequence

TMPO
ENST00000266732.8 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.21
Variant links:
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0386132).
BS2
High AC in GnomAdExome4 at 95 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMPONM_001032283.3 linkuse as main transcriptc.565+1449A>G intron_variant ENST00000556029.6 NP_001027454.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMPOENST00000556029.6 linkuse as main transcriptc.565+1449A>G intron_variant 1 NM_001032283.3 ENSP00000450627 P42167-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
250884
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135676
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:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000650
AC:
95
AN:
1461740
Hom.:
0
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
727176
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:
0.0000845
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000227
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 10, 2023The p.R344G variant (also known as c.1030A>G), located in coding exon 4 of the TMPO gene, results from an A to G substitution at nucleotide position 1030. The arginine at codon 344 is replaced by glycine, an amino acid with dissimilar 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 344 of the TMPO protein (p.Arg344Gly). This variant is present in population databases (rs754951098, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TMPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 574819). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TMPO protein function. 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 submitterclinical testingGeneDxJun 17, 2019Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.0066
T
MetaRNN
Benign
0.039
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.28
N
REVEL
Benign
0.040
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.026
D
Polyphen
0.18
B
Vest4
0.077
MVP
0.16
MPC
0.086
ClinPred
0.085
T
GERP RS
2.1
Varity_R
0.082
gMVP
0.14

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: rs754951098; hg19: chr12-98927065; API