Genetic Variant NM_001081550.2:c.769-11delT (chrX-123671771-TA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001081550.2(THOC2):c.769-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 999,454 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0038 ( 0 hom. 3 hem. )

Consequence

THOC2
NM_001081550.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

107604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000336

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:

0.0000388

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00669

AC:

696

AN:

104086

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00452

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.00935

Gnomad FIN exome

AF:

0.00355

Gnomad NFE exome

AF:

0.00514

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.00384

AC:

3424

AN:

891818

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

256168

show subpopulations

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

African (AFR)

AF:

0.00444

AC:

AN:

20738

American (AMR)

AF:

0.00834

AC:

204

AN:

24446

Ashkenazi Jewish (ASJ)

AF:

0.00437

AC:

AN:

14883

East Asian (EAS)

AF:

0.00282

AC:

AN:

24825

South Asian (SAS)

AF:

0.00391

AC:

146

AN:

37322

European-Finnish (FIN)

AF:

0.00279

AC:

AN:

34711

Middle Eastern (MID)

AF:

0.00215

AC:

AN:

3253

European-Non Finnish (NFE)

AF:

0.00373

AC:

2588

AN:

694421

Other (OTH)

AF:

0.00416

AC:

155

AN:

37219

⚠️ 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: 0.246

Heterozygous variant carriers

520

1040

1561

2081

2601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.0000372

AC:

AN:

107636

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31398

show subpopulations

African (AFR)

AF:

0.0000336

AC:

AN:

29796

American (AMR)

AF:

0.00

AC:

AN:

10096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2578

East Asian (EAS)

AF:

0.00

AC:

AN:

3461

South Asian (SAS)

AF:

0.00

AC:

AN:

2541

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5275

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000388

AC:

AN:

51556

Other (OTH)

AF:

0.000690

AC:

AN:

1450

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

Age Distribution

Genome Het

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:

0.0140

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.59

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over