rs775680174

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4BP6_ModerateBS2

The NM_001081550.2(THOC2):c.4756C>T(p.His1586Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,207,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000037 ( 0 hom. 14 hem. )

Consequence

THOC2
NM_001081550.2 missense, splice_region

Scores

Splicing: ADA: 0.9006

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 8.75

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 -6 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=0.29476).

BP6

Variant X-123610962-G-A is Benign according to our data. Variant chrX-123610962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2429418.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.4756C>T	p.His1586Tyr	missense_variant, splice_region_variant	Exon 38 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.4756C>T	p.His1586Tyr	missense_variant, splice_region_variant	Exon 38 of 39	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.4756C>T	p.His1586Tyr	missense_variant, splice_region_variant	Exon 38 of 39	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.4411C>T	p.His1471Tyr	missense_variant, splice_region_variant	Exon 34 of 34	5		ENSP00000419795.1	A0A0C4DG98
THOC2	ENST00000441692.5 link	c.1138C>T	p.His380Tyr	missense_variant, splice_region_variant	Exon 9 of 10	5		ENSP00000415211.1	H0Y7U4
THOC2	ENST00000448128.5 link	c.541C>T	p.His181Tyr	missense_variant, splice_region_variant	Exon 8 of 9	5		ENSP00000397317.1	H0Y594
THOC2	ENST00000432353.5 link	n.*998C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 9	1		ENSP00000415947.1	H7C477
THOC2	ENST00000432353.5 link	n.*998C>T		3_prime_UTR_variant	Exon 8 of 9	1		ENSP00000415947.1	H7C477
THOC2	ENST00000416618.5 link	c.522-5C>T		splice_region_variant, intron_variant	Intron 6 of 7	5		ENSP00000415244.1	B7ZBA0
THOC2	ENST00000455053.5 link	c.234-5C>T		splice_region_variant, intron_variant	Intron 2 of 3	3		ENSP00000402168.1	B7ZB98

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111928

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000562

AC:

AN:

178024

AF XY:

0.0000156

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000374

AC:

AN:

1095752

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

361234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26290

American (AMR)

AF:

0.00

AC:

AN:

34829

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19341

East Asian (EAS)

AF:

0.00

AC:

AN:

30062

South Asian (SAS)

AF:

0.00

AC:

AN:

53777

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000464

AC:

AN:

840801

Other (OTH)

AF:

0.0000435

AC:

AN:

46002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111928

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30755

American (AMR)

AF:

0.00

AC:

AN:

10566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00

AC:

AN:

2684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6045

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53224

Other (OTH)

AF:

0.00

AC:

AN:

1506

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome

Benign:1

May 20, 2024

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

T;.;T;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;T;.;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.14

N;.;N;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.040

N;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.52

T;.;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.98

D;.;D;.

Vest4

0.51

MVP

0.75

MPC

0.94

ClinPred

0.80

GERP RS

5.7

Varity_R

0.19

gMVP

0.026

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.90

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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rs775680174

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