X-123614098-C-T

Variant names:

• chrX-123614098-C-T
• NM_001081550.2:c.4403G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001081550.2(THOC2):​c.4403G>A​(p.Arg1468Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.64
• 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 5.5258 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked intellectual disability-short stature-overweight syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27959937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4403G>A	p.Arg1468Lys	missense_variant	Exon 34 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.4403G>A	p.Arg1468Lys	missense_variant	Exon 34 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4403G>A	p.Arg1468Lys	missense_variant	Exon 34 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4058G>A	p.Arg1353Lys	missense_variant	Exon 30 of 34	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.785G>A	p.Arg262Lys	missense_variant	Exon 5 of 10	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.188G>A	p.Arg63Lys	missense_variant	Exon 4 of 9	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.170G>A	p.Arg57Lys	missense_variant	Exon 3 of 8	5		ENSP00000415244.1
THOC2	ENST00000432353.5	n.*645G>A		non_coding_transcript_exon_variant	Exon 4 of 9	1		ENSP00000415947.1
THOC2	ENST00000432353.5	n.*645G>A		3_prime_UTR_variant	Exon 4 of 9	1		ENSP00000415947.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Nov 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nov 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt THOC2 protein function. This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1468 of the THOC2 protein (p.Arg1468Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with THOC2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;.;.;T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T;T;T;.;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;.;.;N;.
PhyloP100		4.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.42	N;.;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.24	T;.;T;T;T
Sift4G	Benign	0.68	T;T;T;T;T
Polyphen		0.0010	B;.;.;B;.
Vest4		0.14
MutPred		0.24		Gain of methylation at R1468 (P = 0.0243);.;.;Gain of methylation at R1468 (P = 0.0243);.;
MVP		0.43
MPC		0.80
ClinPred		0.69	D
GERP RS		6.1
Varity_R		0.25
gMVP		0.088
Mutation Taster		=75/25	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

hg19: chrX-122747949;