Genetic Variant THOC2:c.769-11dupT (chrX-123671771-T-TA) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001081550.2(THOC2):c.769-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,006,010 control chromosomes in the GnomAD database, including 10 homozygotes. There are 290 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 59 hem., cov: 23)

Exomes 𝑓: 0.0048 ( 10 hom. 231 hem. )

Consequence

THOC2
NM_001081550.2 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.586

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant X-123671771-T-TA is Benign according to our data. Variant chrX-123671771-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00158 (170/107659) while in subpopulation SAS AF = 0.0205 (52/2541). AF 95% confidence interval is 0.016. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 59 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.769-11dupT		intron_variant	Intron 8 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.769-11_769-10insT	intron_variant	Intron 8 of 38	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.769-11_769-10insT	intron_variant	Intron 8 of 38	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.424-11_424-10insT	intron_variant	Intron 4 of 33	5		ENSP00000419795.1	A0A0C4DG98
THOC2	ENST00000433883.1 link	n.399-11_399-10insT	intron_variant	Intron 8 of 9	5		ENSP00000415374.1	F2Z2V2

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

171

AN:

107628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000135

Gnomad AMI

AF:

0.00149

Gnomad AMR

AF:

0.00278

Gnomad ASJ

AF:

0.00659

Gnomad EAS

AF:

0.000288

Gnomad SAS

AF:

0.0212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0212

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00279

GnomAD2 exomes

AF:

0.00638

AC:

664

AN:

104086

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.00440

Gnomad AMR exome

AF:

0.00996

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.00495

Gnomad FIN exome

AF:

0.000865

Gnomad NFE exome

AF:

0.00406

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.00485

AC:

4355

AN:

898351

Hom.:

Cov.:

AF XY:

0.000893

AC XY:

231

AN XY:

258813

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00379

AC:

AN:

20870

American (AMR)

AF:

0.00646

AC:

160

AN:

24760

Ashkenazi Jewish (ASJ)

AF:

0.00716

AC:

108

AN:

15083

East Asian (EAS)

AF:

0.00254

AC:

AN:

25176

South Asian (SAS)

AF:

0.0183

AC:

691

AN:

37800

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

35008

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

3266

European-Non Finnish (NFE)

AF:

0.00419

AC:

2927

AN:

698923

Other (OTH)

AF:

0.00593

AC:

222

AN:

37465

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.301

Heterozygous variant carriers

459

918

1377

1836

2295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

170

AN:

107659

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

AN XY:

31413

show subpopulations

African (AFR)

AF:

0.000134

AC:

AN:

29794

American (AMR)

AF:

0.00277

AC:

AN:

10102

Ashkenazi Jewish (ASJ)

AF:

0.00659

AC:

AN:

2578

East Asian (EAS)

AF:

0.000289

AC:

AN:

3461

South Asian (SAS)

AF:

0.0205

AC:

AN:

2541

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5280

Middle Eastern (MID)

AF:

0.0235

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

51569

Other (OTH)

AF:

0.00275

AC:

AN:

1452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0106

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.59

Mutation Taster

=100/0

polymorphism (auto)

(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

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X-123671771-TAAAAAA-TAAAAAAA

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