X-123613430-T-C

Position:

• chrX-123613430-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001081550.2(THOC2):​c.4646A>G​(p.Lys1549Arg) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.66

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20471242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC2	NM_001081550.2	c.4646A>G	p.Lys1549Arg	missense_variant	36/39	ENST00000245838.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC2	ENST00000245838.13	c.4646A>G	p.Lys1549Arg	missense_variant	36/39	5	NM_001081550.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

Sydney Children's Hospital, SCHN

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.;.;.;T;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.52	N;.;D;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.24	T;.;T;T;T;T
Sift4G	Benign	0.60	T;T;T;D;T;T
Polyphen		0.0050	B;.;.;.;B;.
Vest4		0.070
MutPred		0.21		Loss of ubiquitination at K1549 (P = 0.027);.;.;.;Loss of ubiquitination at K1549 (P = 0.027);.;
MVP		0.43
MPC		0.86
ClinPred		0.60	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.19
gMVP		0.039

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1603229932; hg19: chrX-122747281;