X-123671771-TAAAAAA-TAAAAA

Variant names:

• chrX-123671771-TA-T
• rs201356571
• NM_001081550.2:c.769-11delT

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.586
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC2	NM_001081550.2	MANE Select	c.769-11delT		intron	N/A	NP_001075019.1
	THOC2	NM_001441235.1		c.769-11delT		intron	N/A	NP_001428164.1
	THOC2	NM_001441236.1		c.769-11delT		intron	N/A	NP_001428165.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC2	ENST00000245838.13	TSL:5 MANE Select	c.769-11delT		intron	N/A	ENSP00000245838.8
	THOC2	ENST00000355725.8	TSL:5	c.769-11delT		intron	N/A	ENSP00000347959.4
	THOC2	ENST00000491737.5	TSL:5	c.424-11delT		intron	N/A	ENSP00000419795.1

Frequencies

GnomAD3 genomes AF: 0.0000279 AC: 3 AN: 107604 Hom.: 0 Cov.: 23

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

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.: 0 Cov.: 17 AF XY: 0.0000117 AC XY: 3 AN XY: 256168

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

African (AFR) AF: 0.00444 AC: 92 AN: 20738

American (AMR) AF: 0.00834 AC: 204 AN: 24446

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 65 AN: 14883

East Asian (EAS) AF: 0.00282 AC: 70 AN: 24825

South Asian (SAS) AF: 0.00391 AC: 146 AN: 37322

European-Finnish (FIN) AF: 0.00279 AC: 97 AN: 34711

Middle Eastern (MID) AF: 0.00215 AC: 7 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000372 AC: 4 AN: 107636 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31398

African (AFR) AF: 0.0000336 AC: 1 AN: 29796

American (AMR) AF: 0.00 AC: 0 AN: 10096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2578

East Asian (EAS) AF: 0.00 AC: 0 AN: 3461

South Asian (SAS) AF: 0.00 AC: 0 AN: 2541

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5275

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000388 AC: 2 AN: 51556

Other (OTH) AF: 0.000690 AC: 1 AN: 1450

Alfa AF: 0.0140 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs201356571; hg19: chrX-122805622; COSMIC: COSV55547563;