12-98515893-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001032283.3(TMPO):​c.26C>T​(p.Ser9Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TMPO
NM_001032283.3 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.06
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]
TMPO-AS1 (HGNC:44158): (TMPO antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.871
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMPONM_001032283.3 linkc.26C>T p.Ser9Leu missense_variant Exon 1 of 9 ENST00000556029.6 NP_001027454.1 P42167-1A0A024RBE7Q59G12

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMPOENST00000556029.6 linkc.26C>T p.Ser9Leu missense_variant Exon 1 of 9 1 NM_001032283.3 ENSP00000450627.1 P42167-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461404
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727034
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:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
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:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.S9L variant (also known as c.26C>T), located in coding exon 1 of the TMPO gene, results from a C to T substitution at nucleotide position 26. The serine at codon 9 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious 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
Dec 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 9 of the TMPO protein (p.Ser9Leu). This variant is not present in population databases (gnomAD no frequency). 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: 2562958). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
Pathogenic
0.64
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;T;T;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D
MetaSVM
Uncertain
0.024
D
MutationAssessor
Benign
1.2
.;.;L;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-4.5
D;D;D;D;D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.028
D;D;D;D;D
Polyphen
0.93
P;.;P;.;.
Vest4
0.74
MutPred
0.58
Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);
MVP
0.79
MPC
0.22
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.76
gMVP
0.45

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: rs1285853015; hg19: chr12-98909671; API