rs1474472931

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001081550.2(THOC2):c.4664C>T(p.Ser1555Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,203,611 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

THOC2
NM_001081550.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.06

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.4664C>T	p.Ser1555Phe	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.4664C>T	p.Ser1555Phe	missense_variant	Exon 36 of 39	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.4664C>T	p.Ser1555Phe	missense_variant	Exon 36 of 39	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.4319C>T	p.Ser1440Phe	missense_variant	Exon 32 of 34	5		ENSP00000419795.1	A0A0C4DG98
THOC2	ENST00000441692.5 link	c.1046C>T	p.Ser349Phe	missense_variant	Exon 7 of 10	5		ENSP00000415211.1	H0Y7U4
THOC2	ENST00000448128.5 link	c.449C>T	p.Ser150Phe	missense_variant	Exon 6 of 9	5		ENSP00000397317.1	H0Y594
THOC2	ENST00000416618.5 link	c.431C>T	p.Ser144Phe	missense_variant	Exon 5 of 8	5		ENSP00000415244.1	B7ZBA0
THOC2	ENST00000455053.5 link	c.143C>T	p.Ser48Phe	missense_variant	Exon 1 of 4	3		ENSP00000402168.1	B7ZB98
THOC2	ENST00000432353.5 link	n.*906C>T		non_coding_transcript_exon_variant	Exon 6 of 9	1		ENSP00000415947.1	H7C477
THOC2	ENST00000432353.5 link	n.*906C>T		3_prime_UTR_variant	Exon 6 of 9	1		ENSP00000415947.1	H7C477

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110970

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:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000564

AC:

AN:

177186

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:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1092641

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359203

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26095

American (AMR)

AF:

0.00

AC:

AN:

34431

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19293

East Asian (EAS)

AF:

0.00

AC:

AN:

30150

South Asian (SAS)

AF:

0.00

AC:

AN:

52983

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40467

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3867

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839503

Other (OTH)

AF:

0.00

AC:

AN:

45852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30621

American (AMR)

AF:

0.00

AC:

AN:

10462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2620

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2623

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5911

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000379

AC:

AN:

52742

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 17, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.036

T;.;.;.;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;.;D

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.48

T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.97

L;.;.;.;L;.

PhyloP100

8.1

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.1

N;.;D;D;N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.017

D;.;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D;D

Polyphen

0.99

D;.;.;.;D;.

Vest4

0.41

MutPred

0.38

Loss of phosphorylation at S1555 (P = 0.0011);.;.;.;Loss of phosphorylation at S1555 (P = 0.0011);.;

MVP

0.53

MPC

1.0

ClinPred

0.61

GERP RS

5.8

PromoterAI

0.016

Neutral

(source)

Varity_R

0.33

gMVP

0.19

Mutation Taster

=78/22

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over