X-123614063-C-G

Variant names:

• chrX-123614063-C-G
• NM_001081550.2:c.4438G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001081550.2(THOC2):​c.4438G>C​(p.Glu1480Gln) 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, single submitter U:1
• Conservation: PhyloP100: 6.75
• 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 1 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=0.25319052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4438G>C	p.Glu1480Gln	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.4438G>C	p.Glu1480Gln	missense_variant	Exon 34 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4438G>C	p.Glu1480Gln	missense_variant	Exon 34 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4093G>C	p.Glu1365Gln	missense_variant	Exon 30 of 34	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.820G>C	p.Glu274Gln	missense_variant	Exon 5 of 10	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.223G>C	p.Glu75Gln	missense_variant	Exon 4 of 9	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.205G>C	p.Glu69Gln	missense_variant	Exon 3 of 8	5		ENSP00000415244.1
THOC2	ENST00000432353.5	n.*680G>C		non_coding_transcript_exon_variant	Exon 4 of 9	1		ENSP00000415947.1
THOC2	ENST00000432353.5	n.*680G>C		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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 04, 2022

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;.;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.81	L;.;.;L;.
PhyloP100		6.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.81	N;.;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.057	T;.;D;T;T
Sift4G	Benign	0.56	T;T;D;T;T
Polyphen		0.53	P;.;.;P;.
Vest4		0.12
MutPred		0.16		Loss of ubiquitination at K1482 (P = 0.0297);.;.;Loss of ubiquitination at K1482 (P = 0.0297);.;
MVP		0.39
MPC		1.2
ClinPred		0.54	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.098
Mutation Taster		=70/30	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-122747914; COSMIC: COSV99833949; COSMIC: COSV99833949;