rs797045020

Variant names:

• chrX-123625935-A-G
• rs797045020
• NM_001081550.2:c.3034T>C

Variant summary

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

The NM_001081550.2(THOC2):​c.3034T>C​(p.Ser1012Pro) 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: 22)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.27

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 the THOC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). GenCC associations: The gene is linked to X-linked intellectual disability-short stature-overweight syndrome.
• PP5: Variant X-123625935-A-G is Pathogenic according to our data. Variant chrX-123625935-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208525.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.3034T>C	p.Ser1012Pro	missense_variant	Exon 25 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.3034T>C	p.Ser1012Pro	missense_variant	Exon 25 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.3034T>C	p.Ser1012Pro	missense_variant	Exon 25 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.2689T>C	p.Ser897Pro	missense_variant	Exon 21 of 34	5		ENSP00000419795.1
THOC2	ENST00000438358.1	c.250T>C	p.Ser84Pro	missense_variant	Exon 2 of 9	5		ENSP00000416639.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.69	P;P;.
Vest4		0.88
MutPred		0.55		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;
MVP		0.82
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.95

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: rs797045020; hg19: chrX-122759786;