chrX-123703499-G-A

Variant names:

• chrX-123703499-G-A
• rs1556302160
• NM_001081550.2:c.229C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP2 PP5

The NM_001081550.2(THOC2):​c.229C>T​(p.Arg77Cys) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003921828: Functional studies on patient cells showed reduced protein levels (PMID:32116545).".

• 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:3 U:3
• Conservation: PhyloP100: 4.35
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003921828: Functional studies on patient cells showed reduced protein levels (PMID: 32116545).
• 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-123703499-G-A is Pathogenic according to our data. Variant chrX-123703499-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488436.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001081550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC2	NM_001081550.2	MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	NP_001075019.1	Q8NI27-1
	THOC2	NM_001441235.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	NP_001428164.1
	THOC2	NM_001441236.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	NP_001428165.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC2	ENST00000245838.13	TSL:5 MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	ENSP00000245838.8	Q8NI27-1
	THOC2	ENST00000355725.8	TSL:5	c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	ENSP00000347959.4	Q8NI27-1
	THOC2	ENST00000931863.1		c.229C>T	p.Arg77Cys	missense	Exon 4 of 39	ENSP00000601922.1

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

African (AFR) AF: 0.00 AC: 0 AN: 25358

American (AMR) AF: 0.00 AC: 0 AN: 34422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18900

East Asian (EAS) AF: 0.00 AC: 0 AN: 29759

South Asian (SAS) AF: 0.00 AC: 0 AN: 50917

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40179

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3935

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 796574

Other (OTH) AF: 0.00 AC: 0 AN: 44279

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	X-linked intellectual disability-short stature-overweight syndrome (4)
-	1	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.57	P
Vest4		0.47
MutPred		0.47		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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

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