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_001441235.1(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_001441235.1 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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441235.1. 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.1147A>G	p.Ile383Val	missense	Exon 11 of 39	NP_001075019.1
	THOC2	NM_001441235.1		c.1147A>G	p.Ile383Val	missense	Exon 11 of 39	NP_001428164.1
	THOC2	NM_001441236.1		c.1147A>G	p.Ile383Val	missense	Exon 11 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.1147A>G	p.Ile383Val	missense	Exon 11 of 39	ENSP00000245838.8
	THOC2	ENST00000355725.8	TSL:5	c.1147A>G	p.Ile383Val	missense	Exon 11 of 39	ENSP00000347959.4
	THOC2	ENST00000491737.5	TSL:5	c.802A>G	p.Ile268Val	missense	Exon 7 of 34	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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.13
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.025	D
Polyphen		0.091	B
Vest4		0.39
MutPred		0.43		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;