rs928293754

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_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. 11/19 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.25

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the THOC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). 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 link	c.1147A>G	p.Ile383Val	missense_variant	Exon 11 of 39	ENST00000245838.13	NP_001075019.1	Q8NI27-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THOC2	ENST00000245838.13 link	c.1147A>G	p.Ile383Val	missense_variant	Exon 11 of 39	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.1147A>G	p.Ile383Val	missense_variant	Exon 11 of 39	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000491737.5 link	c.802A>G	p.Ile268Val	missense_variant	Exon 7 of 34	5		ENSP00000419795.1	A0A0C4DG98

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000590

AC:

AN:

169615

Hom.:

AF XY:

0.0000176

AC XY:

AN XY:

56687

show subpopulations

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 SAS 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:

AN:

1089227

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

355673

show subpopulations

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:

0.0000191

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000358

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

T;T;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Benign

0.0033

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;L;.

PrimateAI

Uncertain

0.60

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

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.16

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over