rs1556302160

chrX-123703499-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP5

The NM_001081550.2(THOC2):c.229C>T(p.Arg77Cys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 4.35

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 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, THOC2
• PP5: Variant X-123703499-G-A is Pathogenic according to our data. Variant chrX-123703499-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488436.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2}. Variant chrX-123703499-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC2	NM_001081550.2	c.229C>T	p.Arg77Cys	missense_variant	4/39	ENST00000245838.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC2	ENST00000245838.13	c.229C>T	p.Arg77Cys	missense_variant	4/39	5	NM_001081550.2	P1
THOC2	ENST00000355725.8	c.229C>T	p.Arg77Cys	missense_variant	4/39	5		P1
THOC2	ENST00000419789.1	n.158C>T		non_coding_transcript_exon_variant	3/4	5
THOC2	ENST00000433883.1	c.229C>T	p.Arg77Cys	missense_variant, NMD_transcript_variant	4/10	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1044323 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 319199

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 14, 2022	0102 - Loss of function is a likely mechanism of disease in this gene and is associated with THOC2-related neurodevelopmental disorder (MIM#300957). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in three individuals with THOC2-related neurodevelopmental disorder, two of them de novo (PMID: 32960281, 29851191, 32116545). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on patient cells showed reduced protein levels (PMID: 32116545). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, no assertion criteria provided	clinical testing	Sydney Children's Hospital, SCHN	Feb 02, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 08, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32116545, 32960281) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.27
Sift	Benign	0.11	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.57	P;P
Vest4		0.47
MutPred		0.47		Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);
MVP		0.74
MPC		1.5
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556302160; hg19: chrX-122837349; COSMIC: COSV55540286;