rs797045019

Positions:

• chrX-123668239-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001081550.2(THOC2):​c.937C>T​(p.Leu313Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THOC2. . Gene score misZ 5.5258 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability-short stature-overweight syndrome.
• PP5: Variant X-123668239-G-A is Pathogenic according to our data. Variant chrX-123668239-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208524.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.937C>T	p.Leu313Phe	missense_variant	10/39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.937C>T	p.Leu313Phe	missense_variant	10/39	5	NM_001081550.2	ENSP00000245838	P1
THOC2	ENST00000355725.8	c.937C>T	p.Leu313Phe	missense_variant	10/39	5		ENSP00000347959	P1
THOC2	ENST00000491737.5	c.592C>T	p.Leu198Phe	missense_variant	6/34	5		ENSP00000419795

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.087	T;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.42	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.054	T;T;T
Polyphen		0.98	D;D;.
Vest4		0.57
MutPred		0.30		Gain of ubiquitination at K312 (P = 0.0918);Gain of ubiquitination at K312 (P = 0.0918);.;
MVP		0.83
MPC		1.2
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.57
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045019; hg19: chrX-122802090;