X-123671771-TAAAAAA-TAAAAAAAAA

Variant names:

• chrX-123671771-T-TAAA
• rs201356571
• NM_001081550.2:c.769-13_769-11dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001081550.2(THOC2):​c.769-13_769-11dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 923,966 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.769-13_769-11dupTTT		intron_variant	Intron 8 of 38	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.769-11_769-10insTTT		intron_variant	Intron 8 of 38	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.769-11_769-10insTTT		intron_variant	Intron 8 of 38	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.424-11_424-10insTTT		intron_variant	Intron 4 of 33	5		ENSP00000419795.1
THOC2	ENST00000433883.1	n.*399-11_*399-10insTTT		intron_variant	Intron 8 of 9	5		ENSP00000415374.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000108 AC: 1 AN: 923966 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 271336

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

African (AFR) AF: 0.00 AC: 0 AN: 21432

American (AMR) AF: 0.00 AC: 0 AN: 25410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15627

East Asian (EAS) AF: 0.0000386 AC: 1 AN: 25893

South Asian (SAS) AF: 0.00 AC: 0 AN: 39598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3353

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 718065

Other (OTH) AF: 0.00 AC: 0 AN: 38620

⚠️ 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.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201356571; hg19: chrX-122805622;