X-123613410-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001081550.2(THOC2):c.4666G>A(p.Gly1556Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000175 in 1,202,814 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

THOC2
NM_001081550.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

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: Likely_benign. The variant received -5 ACMG points.

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=0.13933074).

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.4666G>A	p.Gly1556Ser	missense_variant	Exon 36 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.4666G>A	p.Gly1556Ser	missense_variant	Exon 36 of 39	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.4666G>A	p.Gly1556Ser	missense_variant	Exon 36 of 39	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.4321G>A	p.Gly1441Ser	missense_variant	Exon 32 of 34	5		ENSP00000419795.1	A0A0C4DG98
THOC2	ENST00000441692.5 link	c.1048G>A	p.Gly350Ser	missense_variant	Exon 7 of 10	5		ENSP00000415211.1	H0Y7U4
THOC2	ENST00000448128.5 link	c.451G>A	p.Gly151Ser	missense_variant	Exon 6 of 9	5		ENSP00000397317.1	H0Y594
THOC2	ENST00000416618.5 link	c.433G>A	p.Gly145Ser	missense_variant	Exon 5 of 8	5		ENSP00000415244.1	B7ZBA0
THOC2	ENST00000455053.5 link	c.145G>A	p.Gly49Ser	missense_variant	Exon 1 of 4	3		ENSP00000402168.1	B7ZB98
THOC2	ENST00000432353.5 link	n.*908G>A		non_coding_transcript_exon_variant	Exon 6 of 9	1		ENSP00000415947.1	H7C477
THOC2	ENST00000432353.5 link	n.*908G>A		3_prime_UTR_variant	Exon 6 of 9	1		ENSP00000415947.1	H7C477

Frequencies

GnomAD3 genomes

AF:

0.0000541

AC:

AN:

110945

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000478

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000283

AC:

AN:

176589

AF XY:

0.0000316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000764

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000758

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1091869

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

358719

show subpopulations

African (AFR)

AF:

0.0000384

AC:

AN:

26019

American (AMR)

AF:

0.000117

AC:

AN:

34280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19287

East Asian (EAS)

AF:

0.0000664

AC:

AN:

30141

South Asian (SAS)

AF:

0.00

AC:

AN:

52845

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40470

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

3826

European-Non Finnish (NFE)

AF:

0.00000477

AC:

AN:

839173

Other (OTH)

AF:

0.00

AC:

AN:

45828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000541

AC:

AN:

110945

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33317

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30621

American (AMR)

AF:

0.000478

AC:

AN:

10463

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2619

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5873

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52754

Other (OTH)

AF:

0.00

AC:

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4666G>A (p.G1556S) alteration is located in exon 36 (coding exon 36) of the THOC2 gene. This alteration results from a G to A substitution at nucleotide position 4666, causing the glycine (G) at amino acid position 1556 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;.;.;.;T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D;D;.;D

M_CAP

Benign

0.083

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.;.;.;L;.

PhyloP100

3.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.82

N;.;D;D;N;N

REVEL

Benign

0.080

Sift

Benign

0.063

T;.;D;T;T;T

Sift4G

Benign

0.088

T;T;T;T;T;T

Polyphen

0.72

P;.;.;.;P;.

Vest4

0.22

MutPred

0.26

Gain of phosphorylation at G1556 (P = 2e-04);.;.;.;Gain of phosphorylation at G1556 (P = 2e-04);.;

MVP

0.41

MPC

0.79

ClinPred

0.080

GERP RS

5.0

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.056

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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.

X-123613410-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over