X-123610962-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_001081550.2(THOC2):c.4756C>T(p.His1586Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,207,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000037 ( 0 hom. 14 hem. )

Consequence

THOC2
NM_001081550.2 missense, splice_region

Scores

Splicing: ADA: 0.9006

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.75

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 0 ACMG points.

PP2

Missense variant where missense usually causes diseases, THOC2

BP4

Computational evidence support a benign effect (MetaRNN=0.29476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC2	NM_001081550.2 linkuse as main transcript	c.4756C>T	p.His1586Tyr	missense_variant, splice_region_variant	38/39	ENST00000245838.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC2	ENST00000245838.13 linkuse as main transcript	c.4756C>T	p.His1586Tyr	missense_variant, splice_region_variant	38/39	5	NM_001081550.2	P1	Q8NI27-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111928

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34102

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000562

AC:

AN:

178024

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

63976

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000374

AC:

AN:

1095752

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

361234

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000464

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111928

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34102

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 08, 2022

The THOC2 c.4756C>T (p.His1586Tyr) missense variant results in the substitution of histidine at amino acid position 1586 with tyrosine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000038 in the European (non-Finnish) population, which includes one hemizygote (version 3.1.2). A second hemizygote is reported in Genome Aggregation Database version 2.1.1. The c.4756C>T variant is located in the RNA binding domain (PMID: 32116545), but the functional impact of the variant is unclear and in silico predictions show mixed results. Based on the available evidence, the c.4756C>T (p.His1586Tyr) variant is classified as a variant of uncertain significance for X-linked intellectual disability-short stature-overweight syndrome. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.022

T;.;T;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;T;.;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.14

N;.;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.040

N;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.52

T;.;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.98

D;.;D;.

Vest4

0.51

MVP

0.75

MPC

0.94

ClinPred

0.80

GERP RS

5.7

Varity_R

0.19

gMVP

0.026

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.90

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