chrX-123613710-T-C

Variant names:

• chrX-123613710-T-C
• rs1556005930
• NM_001081550.2:c.4450-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001081550.2(THOC2):​c.4450-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: THOC2 NM_001081550.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.42
• Publications: 3 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-123613710-T-C is Pathogenic according to our data. Variant chrX-123613710-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 488434.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4450-2A>G		splice_acceptor_variant, intron_variant	Intron 34 of 38	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.4450-2A>G		splice_acceptor_variant, intron_variant	Intron 34 of 38	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4450-2A>G		splice_acceptor_variant, intron_variant	Intron 34 of 38	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4105-2A>G		splice_acceptor_variant, intron_variant	Intron 30 of 33	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.832-2A>G		splice_acceptor_variant, intron_variant	Intron 5 of 9	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.235-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 8	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.217-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 7	5		ENSP00000415244.1
THOC2	ENST00000432353.5	n.*692-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 8	1		ENSP00000415947.1
THOC2	ENST00000455053.5	c.-156A>G		upstream_gene_variant		3		ENSP00000402168.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome Pathogenic:2

Oct 16, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2018

Sydney Children's Hospital, SCHN

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 32116545, 29851191, 34976470) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.4
GERP RS		5.3
PromoterAI		0.011	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs1556005930; hg19: chrX-122747561;