rs773867484

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001081550.2(THOC2):c.4703T>C(p.Ile1568Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000169 in 1,185,201 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

THOC2
NM_001081550.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68

Publications

0 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 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.090459764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.4703T>C	p.Ile1568Thr	missense_variant	Exon 37 of 39	ENST00000245838.13	NP_001075019.1	Q8NI27-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THOC2	ENST00000245838.13 link	c.4703T>C	p.Ile1568Thr	missense_variant	Exon 37 of 39	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.4703T>C	p.Ile1568Thr	missense_variant	Exon 37 of 39	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.4358T>C	p.Ile1453Thr	missense_variant	Exon 33 of 34	5		ENSP00000419795.1	A0A0C4DG98
THOC2	ENST00000441692.5 link	c.1085T>C	p.Ile362Thr	missense_variant	Exon 8 of 10	5		ENSP00000415211.1	H0Y7U4
THOC2	ENST00000448128.5 link	c.488T>C	p.Ile163Thr	missense_variant	Exon 7 of 9	5		ENSP00000397317.1	H0Y594
THOC2	ENST00000416618.5 link	c.470T>C	p.Ile157Thr	missense_variant	Exon 6 of 8	5		ENSP00000415244.1	B7ZBA0
THOC2	ENST00000455053.5 link	c.182T>C	p.Ile61Thr	missense_variant	Exon 2 of 4	3		ENSP00000402168.1	B7ZB98
THOC2	ENST00000432353.5 link	n.*945T>C		non_coding_transcript_exon_variant	Exon 7 of 9	1		ENSP00000415947.1	H7C477
THOC2	ENST00000432353.5 link	n.*945T>C		3_prime_UTR_variant	Exon 7 of 9	1		ENSP00000415947.1	H7C477

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110917

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000556

AC:

AN:

179726

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.31e-7

AC:

AN:

1074284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

341910

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25974

American (AMR)

AF:

0.00

AC:

AN:

35086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19203

East Asian (EAS)

AF:

0.00

AC:

AN:

30074

South Asian (SAS)

AF:

0.00

AC:

AN:

53395

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

821017

Other (OTH)

AF:

0.00

AC:

AN:

45345

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000902

AC:

AN:

110917

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33149

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30490

American (AMR)

AF:

0.00

AC:

AN:

10353

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52972

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 29, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.063

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.016

T;.;.;.;T;T

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.86

D;T;T;T;.;D

M_CAP

Benign

0.0037

MetaRNN

Benign

0.090

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

N;.;.;.;N;.

PhyloP100

4.7

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.17

N;.;D;N;N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;.;T;T;T;T

Sift4G

Benign

0.59

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;B;.

Vest4

0.13

MutPred

0.29

Gain of phosphorylation at I1568 (P = 0.0024);.;.;.;Gain of phosphorylation at I1568 (P = 0.0024);.;

MVP

0.13

MPC

0.99

ClinPred

0.16

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.0047

Mutation Taster

=90/10

polymorphism

(source)

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

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rs773867484

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over