NM_001081550.2:c.4703T>C

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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NM_001081550.2:c.4703T>C

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