rs199795381

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_024339.5(THOC6):c.569G>A(p.Gly190Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000213 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

THOC6
NM_024339.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:1

Conservation

PhyloP100: 5.69

Publications

3 publications found

Variant links:

Genes affected

THOC6 (HGNC:28369): (THO complex subunit 6) This gene encodes a subunit of the multi-protein THO complex, which is involved in coordination between transcription and mRNA processing. The THO complex is a component of the TREX (transcription/export) complex, which is involved in transcription and export of mRNAs. A missense mutation in this gene is associated with a neurodevelopmental disorder called Beaulieu-Boycott-Innes syndrome. [provided by RefSeq, Dec 2016]

THOC6 Gene-Disease associations (from GenCC):

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

THOC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 16-3026764-G-A is Pathogenic according to our data. Variant chr16-3026764-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 561208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
THOC6	NM_024339.5 link	c.569G>A	p.Gly190Glu	missense_variant	Exon 8 of 13	ENST00000326266.13	NP_077315.2
THOC6	NM_001347704.2 link	c.569G>A	p.Gly190Glu	missense_variant	Exon 9 of 14		NP_001334633.1
THOC6	NM_001347703.2 link	c.497G>A	p.Gly166Glu	missense_variant	Exon 9 of 14		NP_001334632.1
THOC6	NM_001142350.3 link	c.569G>A	p.Gly190Glu	missense_variant	Exon 8 of 12		NP_001135822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC6	ENST00000326266.13 link	c.569G>A	p.Gly190Glu	missense_variant	Exon 8 of 13	1	NM_024339.5	ENSP00000326531.8

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000100

AC:

AN:

250076

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000221

AC:

323

AN:

1461648

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000283

AC:

315

AN:

1111882

Other (OTH)

AF:

0.000132

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome

Pathogenic:3Uncertain:1Other:1

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous missense variant was identified, NM_024339.4(THOC6):c.569G>A in exon 8 of 13 of the THOC6 gene. This substitution is predicted to cause a moderate amino acid change from glycine to glutamic acid at position 190 of the protein, NP_077315.2(THOC6):p.(Gly190Glu). The glycine at this position has high conservation (100 vertebrates, UCSC), and is located in the WD4 functional domain. In silico software predicts the missense variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0002% (28 heterozygotes, 0 homozygotes). It has been previously reported in patients with Beaulieu-Boycott-Innes syndrome (ClinVar, Amos, J. et al (2017), Mattioli, F. et al (2019)). In addition, functional studies show that this variant causes abnormal nuclear localisation and decreased THOC1/THOC5 interaction (Mattioli, F. et al (2019)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -

Jan 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Nov 07, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 17, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:4

May 09, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect where G190E is detrimental to protein function (PMID: 30476144); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30476144, 31421288, 31216405, 34740920, 27102954) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

THOC6-related disorder

Pathogenic:1

Jan 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The THOC6 c.569G>A variant is predicted to result in the amino acid substitution p.Gly190Glu. This variant was reported in the compound heterozygous state in at least three unrelated individuals with intellectual disability and/or neurodevelopmental phenotypes (Amos et al. 2017. PubMed ID: 27102954; Mattioli et al. 2019. PubMed ID: 30476144; Liu et al. 2019. PubMed ID: 31216405). Functional studies showed that this variant results in abnormal subcellular localization and impaired protein-protein interaction (Mattioli et al. 2019. PubMed ID: 30476144). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3076765-G-A). This variant is interpreted as likely pathogenic. -

Intellectual disability

Pathogenic:1

Sep 22, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.5

M;.;.;M

PhyloP100

5.7

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-8.0

D;.;.;D

REVEL

Pathogenic

0.65

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.98

MVP

0.90

MPC

0.56

ClinPred

0.75

GERP RS

5.6

Varity_R

0.93

gMVP

0.82

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over