rs2046785257

Variant names:

• chrX-123613636-T-C
• rs2046785257
• NM_001081550.2:c.4519+3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001081550.2(THOC2):​c.4519+3A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: THOC2 NM_001081550.2 splice_region, intron
• Scores: Splicing: ADA: 0.9940
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4519+3A>G		splice_region_variant, intron_variant	Intron 35 of 38	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.4519+3A>G		splice_region_variant, intron_variant	Intron 35 of 38	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4519+3A>G		splice_region_variant, intron_variant	Intron 35 of 38	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4174+3A>G		splice_region_variant, intron_variant	Intron 31 of 33	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.901+3A>G		splice_region_variant, intron_variant	Intron 6 of 9	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.304+3A>G		splice_region_variant, intron_variant	Intron 5 of 8	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.286+3A>G		splice_region_variant, intron_variant	Intron 4 of 7	5		ENSP00000415244.1
THOC2	ENST00000432353.5	n.*761+3A>G		splice_region_variant, intron_variant	Intron 5 of 8	1		ENSP00000415947.1
THOC2	ENST00000455053.5	c.-82A>G		upstream_gene_variant		3		ENSP00000402168.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome Uncertain:1

Jan 04, 2022

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited c.4519+3A>G variant identified in THOC2 has not previously been reported in the literature or public variant repositories (ClinVar andLOVD). This variant is absent from gnomAD v2.1.1 and v3.1.2 datasets and is observed in two alleles (one homozygote) with ~0.0008% minor allele frequency in TOPMed Freeze 8 dataset, suggesting it is not a common benign variant in the populations represented in those databases. The c.4519+3A>G variant is located in the donor splice region of exon 35 of this 39-exon gene. In silico algorithms slightly predict gain of a possible new splice donor site at 3 base-pair downstream of the variant (Splice AI= 0.21) [PMIDs:30661751]. Based on available evidence this maternally inherited c.4519+3A>G variant in THOC2 is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		6.6
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 3

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

Other links and lift over

dbSNP: rs2046785257; hg19: chrX-122747487;