rs181749437

Variant names:

• chrX-123712831-A-T
• rs181749437
• NM_001081550.2:c.130+19T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001441235.1(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_001441235.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.383
• Publications: 0 publications found

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

ACMG classification

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_001441235.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC2	NM_001081550.2	MANE Select	c.130+19T>A		intron	N/A	NP_001075019.1
	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

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

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 749 AN: 112154 Hom.: 10 Cov.: 23

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

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.: 5 Cov.: 15 AF XY: 0.000587 AC XY: 162 AN XY: 275756

African (AFR) AF: 0.0258 AC: 576 AN: 22286

American (AMR) AF: 0.00143 AC: 33 AN: 23153

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16582

East Asian (EAS) AF: 0.00 AC: 0 AN: 29071

South Asian (SAS) AF: 0.0000669 AC: 3 AN: 44832

European-Finnish (FIN) AF: 0.0000762 AC: 3 AN: 39345

Middle Eastern (MID) AF: 0.00135 AC: 5 AN: 3696

European-Non Finnish (NFE) AF: 0.0000149 AC: 11 AN: 735905

Other (OTH) AF: 0.00159 AC: 65 AN: 40838

GnomAD4 genome AF: 0.00676 AC: 758 AN: 112207 Hom.: 10 Cov.: 23 AF XY: 0.00605 AC XY: 208 AN XY: 34385

African (AFR) AF: 0.0226 AC: 699 AN: 30947

American (AMR) AF: 0.00380 AC: 40 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3605

South Asian (SAS) AF: 0.00 AC: 0 AN: 2704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53257

Other (OTH) AF: 0.00917 AC: 14 AN: 1526

Alfa AF: 0.00305 Hom.: 15

Bravo AF: 0.00820

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.5
DANN	Benign	0.77
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs181749437; hg19: chrX-122846681;