rs797045019

Variant names:

• chrX-123668239-G-A
• rs797045019
• NM_001081550.2:c.937C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. L313L) has been classified as Likely benign.

• 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
• Publications: 4 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 4 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.
• PP5: Variant X-123668239-G-A is Pathogenic according to our data. Variant chrX-123668239-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208524.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.937C>T	p.Leu313Phe	missense_variant	Exon 10 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.937C>T	p.Leu313Phe	missense_variant	Exon 10 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.937C>T	p.Leu313Phe	missense_variant	Exon 10 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.592C>T	p.Leu198Phe	missense_variant	Exon 6 of 34	5		ENSP00000419795.1
THOC2	ENST00000433883.1	n.*567C>T		downstream_gene_variant		5		ENSP00000415374.1

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

Aug 06, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.
PhyloP100		9.1
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
Mutation Taster		=23/77	disease causing (ClinVar)

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

dbSNP: rs797045019; hg19: chrX-122802090;