Genetic Variant THOC2:c.130+19T>A (chrX-123712831-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001081550.2(THOC2):c.130+19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,067,915 control chromosomes in the GnomAD database, including 15 homozygotes. There are 370 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 0.0068 ( 10 hom., 208 hem., cov: 23)

Exomes 𝑓: 0.00073 ( 5 hom. 162 hem. )

Consequence

THOC2
NM_001081550.2 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.383

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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, Ambry Genetics

THOC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

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

BP6

Variant X-123712831-A-T is Benign according to our data. Variant chrX-123712831-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445452.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00676 (758/112207) while in subpopulation AFR AF = 0.0226 (699/30947). AF 95% confidence interval is 0.0212. There are 10 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THOC2	NM_001081550.2	MANE Select	c.130+19T>A	intron	N/A	NP_001075019.1	Q8NI27-1
THOC2	NM_001441235.1		c.130+19T>A	intron	N/A	NP_001428164.1
THOC2	NM_001441236.1		c.130+19T>A	intron	N/A	NP_001428165.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THOC2	ENST00000245838.13	TSL:5 MANE Select	c.130+19T>A	intron	N/A	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8	TSL:5	c.130+19T>A	intron	N/A	ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000931863.1		c.130+19T>A	intron	N/A	ENSP00000601922.1

Frequencies

GnomAD3 genomes

AF:

0.00668

AC:

749

AN:

112154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

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:

0.0000939

Gnomad OTH

AF:

0.00929

GnomAD2 exomes

AF:

0.00229

AC:

310

AN:

135638

AF XY:

0.00140

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.000972

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000709

Gnomad NFE exome

AF:

0.0000308

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000728

AC:

696

AN:

955708

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

162

AN XY:

275756

show subpopulations

African (AFR)

AF:

0.0258

AC:

576

AN:

22286

American (AMR)

AF:

0.00143

AC:

AN:

23153

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16582

East Asian (EAS)

AF:

0.00

AC:

AN:

29071

South Asian (SAS)

AF:

0.0000669

AC:

AN:

44832

European-Finnish (FIN)

AF:

0.0000762

AC:

AN:

39345

Middle Eastern (MID)

AF:

0.00135

AC:

AN:

3696

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

735905

Other (OTH)

AF:

0.00159

AC:

AN:

40838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00676

AC:

758

AN:

112207

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

208

AN XY:

34385

show subpopulations

African (AFR)

AF:

0.0226

AC:

699

AN:

30947

American (AMR)

AF:

0.00380

AC:

AN:

10536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3605

South Asian (SAS)

AF:

0.00

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000939

AC:

AN:

53257

Other (OTH)

AF:

0.00917

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

103

129

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:

0.00305

Hom.:

Bravo

AF:

0.00820

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

8.5

(source)

DANN

Benign

0.77

PhyloP100

0.38

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over