Genetic Variant THOC2:c.4449+18T>A (chrX-123614034-A-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001081550.2(THOC2):c.4449+18T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,074,282 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000019 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

THOC2
NM_001081550.2 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0190

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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-123614034-A-T is Benign according to our data. Variant chrX-123614034-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3768831.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.4449+18T>A		intron_variant	Intron 34 of 38	ENST00000245838.13	NP_001075019.1	Q8NI27-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
THOC2	ENST00000245838.13 link	c.4449+18T>A	intron_variant	Intron 34 of 38	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.4449+18T>A	intron_variant	Intron 34 of 38	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.4104+18T>A	intron_variant	Intron 30 of 33	5		ENSP00000419795.1	A0A0C4DG98
THOC2	ENST00000441692.5 link	c.831+18T>A	intron_variant	Intron 5 of 9	5		ENSP00000415211.1	H0Y7U4
THOC2	ENST00000448128.5 link	c.234+18T>A	intron_variant	Intron 4 of 8	5		ENSP00000397317.1	H0Y594
THOC2	ENST00000416618.5 link	c.216+18T>A	intron_variant	Intron 3 of 7	5		ENSP00000415244.1	B7ZBA0
THOC2	ENST00000432353.5 link	n.*691+18T>A	intron_variant	Intron 4 of 8	1		ENSP00000415947.1	H7C477

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000958

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

GnomAD4 exome

AF:

0.00000186

AC:

AN:

1074282

Hom.:

Cov.:

AF XY:

0.00000575

AC XY:

AN XY:

348006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25711

American (AMR)

AF:

0.00

AC:

AN:

33562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18614

East Asian (EAS)

AF:

0.00

AC:

AN:

29986

South Asian (SAS)

AF:

0.00

AC:

AN:

51319

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33337

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4037

European-Non Finnish (NFE)

AF:

0.00000240

AC:

AN:

832421

Other (OTH)

AF:

0.00

AC:

AN:

45295

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000900

AC:

AN:

111142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30745

American (AMR)

AF:

0.0000958

AC:

AN:

10436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

2627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52726

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.91

(source)

DANN

Benign

0.39

PhyloP100

-0.019

PromoterAI

-0.0088

Neutral

(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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X-123614034-A-T

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