rs928293754

Variant names:

• chrX-123667149-T-C
• rs928293754
• NM_001081550.2:c.1147A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001081550.2(THOC2):​c.1147A>G​(p.Ile383Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,089,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• 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: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25434327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2	c.1147A>G	p.Ile383Val	missense_variant	Exon 11 of 39	ENST00000245838.13	NP_001075019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC2	ENST00000245838.13	c.1147A>G	p.Ile383Val	missense_variant	Exon 11 of 39	5	NM_001081550.2	ENSP00000245838.8
THOC2	ENST00000355725.8	c.1147A>G	p.Ile383Val	missense_variant	Exon 11 of 39	5		ENSP00000347959.4
THOC2	ENST00000491737.5	c.802A>G	p.Ile268Val	missense_variant	Exon 7 of 34	5		ENSP00000419795.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000590 AC: 1 AN: 169615 AF XY: 0.0000176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000367 AC: 4 AN: 1089227 Hom.: 0 Cov.: 27 AF XY: 0.00000281 AC XY: 1 AN XY: 355673

African (AFR) AF: 0.00 AC: 0 AN: 26012

American (AMR) AF: 0.00 AC: 0 AN: 33920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19069

East Asian (EAS) AF: 0.00 AC: 0 AN: 29903

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52257

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40339

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 837869

Other (OTH) AF: 0.00 AC: 0 AN: 45759

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1147A>G (p.I383V) alteration is located in exon 11 (coding exon 11) of the THOC2 gene. This alteration results from an A to G substitution at nucleotide position 1147, causing the isoleucine (I) at amino acid position 383 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (1/169615) total alleles studied. The highest observed frequency was 0.001% (1/77581) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T;T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;L;.
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.80	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.091	B;B;.
Vest4		0.39
MutPred		0.43		Loss of ubiquitination at K385 (P = 0.0853);Loss of ubiquitination at K385 (P = 0.0853);.;
MVP		0.43
MPC		0.92
ClinPred		0.40	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.16
Mutation Taster		=92/8	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: rs928293754; hg19: chrX-122801000;