X-123613660-G-A

Variant names:

• chrX-123613660-G-A
• rs987969946
• NM_001081550.2:c.4498C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001081550.2(THOC2):​c.4498C>T​(p.Arg1500Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.97
• 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
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4498C>T	p.Arg1500Cys	missense_variant	Exon 35 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.4498C>T	p.Arg1500Cys	missense_variant	Exon 35 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4498C>T	p.Arg1500Cys	missense_variant	Exon 35 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4153C>T	p.Arg1385Cys	missense_variant	Exon 31 of 34	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.880C>T	p.Arg294Cys	missense_variant	Exon 6 of 10	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.283C>T	p.Arg95Cys	missense_variant	Exon 5 of 9	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.265C>T	p.Arg89Cys	missense_variant	Exon 4 of 8	5		ENSP00000415244.1
THOC2	ENST00000432353.5	n.*740C>T		non_coding_transcript_exon_variant	Exon 5 of 9	1		ENSP00000415947.1
THOC2	ENST00000432353.5	n.*740C>T		3_prime_UTR_variant	Exon 5 of 9	1		ENSP00000415947.1
THOC2	ENST00000455053.5	c.-106C>T		upstream_gene_variant		3		ENSP00000402168.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4498C>T (p.R1500C) alteration is located in exon 35 (coding exon 35) of the THOC2 gene. This alteration results from a C to T substitution at nucleotide position 4498, causing the arginine (R) at amino acid position 1500 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T;.;.;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.97	L;.;.;L;.
PhyloP100		5.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;.;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.28
MutPred		0.31		Loss of MoRF binding (P = 0.0412);.;.;Loss of MoRF binding (P = 0.0412);.;
MVP		0.54
MPC		2.1
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.20
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs987969946; hg19: chrX-122747511;