dbSNP rs797045018: THOC2:p.Leu438Pro (chrX-123665715-A-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001081550.2(THOC2):c.1313T>C(p.Leu438Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

THOC2
NM_001081550.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.32

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant X-123665715-A-G is Pathogenic according to our data. Variant chrX-123665715-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 208523.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.1313T>C	p.Leu438Pro	missense_variant	Exon 12 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
THOC2	ENST00000245838.13 link	c.1313T>C	p.Leu438Pro	missense_variant	Exon 12 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8 link	c.1313T>C	p.Leu438Pro	missense_variant	Exon 12 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5 link	c.968T>C	p.Leu323Pro	missense_variant	Exon 8 of 34	5		ENSP00000419795.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1091237

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357485

African (AFR)

AF:

0.00

AC:

AN:

26323

American (AMR)

AF:

0.00

AC:

AN:

34992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19190

East Asian (EAS)

AF:

0.00

AC:

AN:

30133

South Asian (SAS)

AF:

0.00

AC:

AN:

52311

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40221

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838161

Other (OTH)

AF:

0.00

AC:

AN:

45795

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome

Pathogenic:1

Aug 06, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

T;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.048

MutationAssessor

Pathogenic

3.2

M;M;.

PhyloP100

9.3

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.76

Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;

MVP

0.95

MPC

2.7

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(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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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