chrX-123610952-G-A

Variant names:

• chrX-123610952-G-A
• rs752066937
• NM_001081550.2:c.4766C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001081550.2(THOC2):​c.4766C>T​(p.Ser1589Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000073 in 1,095,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1589S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.87
• 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: Likely_benign. The variant received -5 ACMG points.

• 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=0.25140375).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.4766C>T	p.Ser1589Leu	missense_variant	Exon 38 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.4766C>T	p.Ser1589Leu	missense_variant	Exon 38 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.4766C>T	p.Ser1589Leu	missense_variant	Exon 38 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.4421C>T	p.Ser1474Leu	missense_variant	Exon 34 of 34	5		ENSP00000419795.1
THOC2	ENST00000441692.5	c.1148C>T	p.Ser383Leu	missense_variant	Exon 9 of 10	5		ENSP00000415211.1
THOC2	ENST00000448128.5	c.551C>T	p.Ser184Leu	missense_variant	Exon 8 of 9	5		ENSP00000397317.1
THOC2	ENST00000416618.5	c.527C>T	p.Ser176Leu	missense_variant	Exon 7 of 8	5		ENSP00000415244.1
THOC2	ENST00000455053.5	c.239C>T	p.Ser80Leu	missense_variant	Exon 3 of 4	3		ENSP00000402168.1
THOC2	ENST00000432353.5	n.*1008C>T		non_coding_transcript_exon_variant	Exon 8 of 9	1		ENSP00000415947.1
THOC2	ENST00000432353.5	n.*1008C>T		3_prime_UTR_variant	Exon 8 of 9	1		ENSP00000415947.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 177144 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000765

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000730 AC: 8 AN: 1095209 Hom.: 0 Cov.: 28 AF XY: 0.00000832 AC XY: 3 AN XY: 360713

African (AFR) AF: 0.00 AC: 0 AN: 26284

American (AMR) AF: 0.0000576 AC: 2 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30064

South Asian (SAS) AF: 0.00 AC: 0 AN: 53602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000714 AC: 6 AN: 840549

Other (OTH) AF: 0.00 AC: 0 AN: 45977

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 09, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T;.;.;.;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;T;T;.;D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L;.;.;.;L;.
PhyloP100		6.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.47	N;.;D;D;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;T;D;D
Polyphen		0.90	P;.;.;.;P;.
Vest4		0.55
MutPred		0.22		Loss of phosphorylation at S1589 (P = 8e-04);.;.;.;Loss of phosphorylation at S1589 (P = 8e-04);.;
MVP		0.30
MPC		0.73
ClinPred		0.51	D
GERP RS		5.7
Varity_R		0.53
gMVP		0.033
Mutation Taster		=90/10	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

dbSNP: rs752066937; hg19: chrX-122744803;