X-123613451-C-G

Variant names:

• chrX-123613451-C-G
• NM_001081550.2:c.4625G>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.4625G>C​(p.Ser1542Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,384 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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=0.09232822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4625G>C	p.Ser1542Thr	missense_variant	Exon 36 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.4625G>C	p.Ser1542Thr	missense_variant	Exon 36 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4625G>C	p.Ser1542Thr	missense_variant	Exon 36 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4280G>C	p.Ser1427Thr	missense_variant	Exon 32 of 34	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.1007G>C	p.Ser336Thr	missense_variant	Exon 7 of 10	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.410G>C	p.Ser137Thr	missense_variant	Exon 6 of 9	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.392G>C	p.Ser131Thr	missense_variant	Exon 5 of 8	5		ENSP00000415244.1
THOC2	ENST00000455053.5	c.104G>C	p.Ser35Thr	missense_variant	Exon 1 of 4	3		ENSP00000402168.1
THOC2	ENST00000432353.5	n.*867G>C		non_coding_transcript_exon_variant	Exon 6 of 9	1		ENSP00000415947.1
THOC2	ENST00000432353.5	n.*867G>C		3_prime_UTR_variant	Exon 6 of 9	1		ENSP00000415947.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096384 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361942

African (AFR) AF: 0.00 AC: 0 AN: 26359

American (AMR) AF: 0.00 AC: 0 AN: 35131

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.00 AC: 0 AN: 53942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840806

Other (OTH) AF: 0.00 AC: 0 AN: 46032

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.022	T;.;.;.;T;T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T;T;T;T;.;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.092	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.47	N;.;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.42	T;.;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;.
Vest4		0.086
MutPred		0.26		Gain of ubiquitination at K1546 (P = 0.1215);.;.;.;Gain of ubiquitination at K1546 (P = 0.1215);.;
MVP		0.29
MPC		0.72
ClinPred		0.12	T
GERP RS		4.9
PromoterAI		-0.0038	Neutral
Varity_R		0.17
gMVP		0.016
Mutation Taster		=93/7	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-122747302;