Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_001081550.2(THOC2):c.229C>T(p.Arg77Cys) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

THOC2
NM_001081550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 4.35

Publications

1 publications found

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]

THOC2 Gene-Disease associations (from GenCC):

X-linked intellectual disability-short stature-overweight syndrome
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

THOC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 5.5258 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked intellectual disability-short stature-overweight syndrome.

PP5

Variant X-123703499-G-A is Pathogenic according to our data. Variant chrX-123703499-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488436.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
THOC2	NM_001081550.2	MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	NP_001075019.1
THOC2	NM_001441235.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	NP_001428164.1
THOC2	NM_001441236.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	NP_001428165.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
THOC2	ENST00000245838.13	TSL:5 MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	ENSP00000245838.8
THOC2	ENST00000355725.8	TSL:5	c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	ENSP00000347959.4
THOC2	ENST00000419789.1	TSL:5	n.158C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1044323

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

319199

African (AFR)

AF:

0.00

AC:

AN:

25358

American (AMR)

AF:

0.00

AC:

AN:

34422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18900

East Asian (EAS)

AF:

0.00

AC:

AN:

29759

South Asian (SAS)

AF:

0.00

AC:

AN:

50917

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40179

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3935

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

796574

Other (OTH)

AF:

0.00

AC:

AN:

44279

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked intellectual disability-short stature-overweight syndrome (4)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

PhyloP100

4.4

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.27

Sift

Benign

0.11

Sift4G

Benign

0.12

Polyphen

0.57

Vest4

0.47

MutPred

0.47

Loss of disorder (P = 0.0157)

MVP

0.74

MPC

1.5

ClinPred

0.97

GERP RS

5.1

Varity_R

0.30

gMVP

0.51

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1556302160

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over