X-123613538-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001081550.2(THOC2):​c.4538A>G​(p.Lys1513Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Consequence

THOC2
NM_001081550.2 missense

Scores

5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.55
Variant links:
Genes affected
THOC2 (HGNC:19073): (THO complex subunit 2) The TREX multiprotein complex binds specifically to spliced mRNAs to facilitate mRNA export. The protein encoded by this gene is a member of the THO complex, a subset of the TREX complex. The encoded protein interacts with the THOC1 protein.[provided by RefSeq, Jun 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THOC2. . Gene score misZ 5.5258 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability-short stature-overweight syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.2518567).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
THOC2NM_001081550.2 linkuse as main transcriptc.4538A>G p.Lys1513Arg missense_variant 36/39 ENST00000245838.13 NP_001075019.1 Q8NI27-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
THOC2ENST00000245838.13 linkuse as main transcriptc.4538A>G p.Lys1513Arg missense_variant 36/395 NM_001081550.2 ENSP00000245838.8 Q8NI27-1
THOC2ENST00000355725.8 linkuse as main transcriptc.4538A>G p.Lys1513Arg missense_variant 36/395 ENSP00000347959.4 Q8NI27-1
THOC2ENST00000491737.5 linkuse as main transcriptc.4193A>G p.Lys1398Arg missense_variant 32/345 ENSP00000419795.1 A0A0C4DG98
THOC2ENST00000441692.5 linkuse as main transcriptc.920A>G p.Lys307Arg missense_variant 7/105 ENSP00000415211.1 H0Y7U4
THOC2ENST00000448128.5 linkuse as main transcriptc.323A>G p.Lys108Arg missense_variant 6/95 ENSP00000397317.1 H0Y594
THOC2ENST00000416618.5 linkuse as main transcriptc.305A>G p.Lys102Arg missense_variant 5/85 ENSP00000415244.1 B7ZBA0
THOC2ENST00000455053.5 linkuse as main transcriptc.17A>G p.Lys6Arg missense_variant 1/43 ENSP00000402168.1 B7ZB98
THOC2ENST00000432353.5 linkuse as main transcriptn.*780A>G non_coding_transcript_exon_variant 6/91 ENSP00000415947.1 H7C477
THOC2ENST00000432353.5 linkuse as main transcriptn.*780A>G 3_prime_UTR_variant 6/91 ENSP00000415947.1 H7C477

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 07, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
23
DANN
Benign
0.94
DEOGEN2
Benign
0.019
T;.;.;.;T;T
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D;D;D;.;D
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.25
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.97
L;.;.;.;L;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.070
N;.;D;N;N;N
REVEL
Uncertain
0.42
Sift
Benign
0.32
T;.;D;T;T;T
Sift4G
Benign
0.85
T;T;T;T;T;T
Polyphen
0.42
B;.;.;.;B;.
Vest4
0.16
MutPred
0.21
Loss of ubiquitination at K1513 (P = 0.0027);.;.;.;Loss of ubiquitination at K1513 (P = 0.0027);.;
MVP
0.51
MPC
1.1
ClinPred
0.68
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.029

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-122747389; API