chr16-3026140-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_024339.5(THOC6):c.298T>A(p.Trp100Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000364 in 1,608,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

THOC6
NM_024339.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 6.68

Publications

11 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: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 16-3026140-T-A is Pathogenic according to our data. Variant chr16-3026140-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521347.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC6	NM_024339.5 link	c.298T>A	p.Trp100Arg	missense_variant	Exon 4 of 13	ENST00000326266.13	NP_077315.2	Q86W42-1
THOC6	NM_001347704.2 link	c.298T>A	p.Trp100Arg	missense_variant	Exon 5 of 14		NP_001334633.1	Q86W42-1
THOC6	NM_001347703.2 link	c.226T>A	p.Trp76Arg	missense_variant	Exon 5 of 14		NP_001334632.1	Q86W42-2
THOC6	NM_001142350.3 link	c.298T>A	p.Trp100Arg	missense_variant	Exon 4 of 12		NP_001135822.1	Q86W42-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC6	ENST00000326266.13 link	c.298T>A	p.Trp100Arg	missense_variant	Exon 4 of 13	1	NM_024339.5	ENSP00000326531.8		Q86W42-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000173

AC:

AN:

248640

AF XY:

0.000209

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000874

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000285

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000381

AC:

555

AN:

1456062

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

260

AN XY:

723386

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33292

American (AMR)

AF:

0.0000225

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25816

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39572

South Asian (SAS)

AF:

0.000198

AC:

AN:

85876

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000463

AC:

513

AN:

1107940

Other (OTH)

AF:

0.000200

AC:

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000204

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000373

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome

Pathogenic:6

Oct 21, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2018

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Beaulieu-Boycott-Innes syndrome (MIM#613680). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (48 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated WD2 repeat (PMID: 30476144). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as likely pathogenic, a VUS and pathogenic (ClinVar, LOVD, Decipher). It has also been reported as part of a haplotype in multiple homozygous or compound heterozygous individuals with intellectual disability (PMID: 30476144, 31421288, 27295358, 35426486, 36900003). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes abnormal protein localization (PMID: 30476144). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) -

Feb 02, 2019

Medgenome Labs Pvt Ltd

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.298T>A(p.Trp100Arg) variant in THOC6 gene has been reported in homozygous state in multiple individuals affected with Beaulieu–Boycott–Innes syndrome (Mattioli F, et. al., 2019; Gupta N, et. al., 2020). Functional studies show that this variant causes abnormal protein localization (Mattioli F, et. al., 2019). The variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic (multiple submissions). The amino acid change p.Trp100Arg in THOC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Trp at position 100 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Oct 03, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.298T>A (p.Trp100Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a rare haplotype (c.298T>A; c.700G>C; c.824G>A) in individuals with Beaulieu-Boycott-Innes syndrome (PMID: 30476144, 27295358, 31216405, 31421288, 33144682, 35426486). Functional studies indicate that the rare haplotype affects nuclear localization of the THOC6 protein and has reduced interaction with protein partners. Additionally, the c.298T>A (p.Trp100Arg) variant alone affects nuclear localization and may contribute to the pathogenicity of the haplotype (PMID: 30476144). The c.298T>A (p.Trp100Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (48/280030) and thus is presumed to be rare. Based on the available evidence, c.298T>A (p.Trp100Arg) is classified as Likely Pathogenic. -

not provided

Pathogenic:2

Nov 09, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional studies of the p.[W100R; G275D; V234L] haplotype suggest a damaging effect with abnormal nuclear localization and decreased interaction with protein partners from the THO complex, and the W100R variant on its own was also suggested to affect nuclear localization of THOC6 (Mattioli et al., 2019); 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: 33144682, 31216405, 31421288, 30476144, 27295358, 26739162, 20503307, 23621916, 27102954, 15998806, 19059247, 11060033) -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Feb 22, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.[298T>A;700G>C;824G>A] (p.[W100R;V234L;G275D]) complex allele affects coding exons 4, 11, and 12 respectively of the THOC6 gene. These alterations make up a known haplotype that results from a T to A substitution at nucleotide position 298, causing the tryptophan (W) at amino acid position 100 to be replaced by an arginine (R), a G to C substitution at nucleotide position 700, causing the valine (V) at amino acid position 234 to be replaced by a leucine (L), and a G to A substitution at nucleotide position 824, causing the glycine (G) at amino acid position 275 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD), the THOC6 c.[298T>A;700G>C;824G>A] haplotype was observed in 0.02% of total alleles studied, with a frequency of 0.03% in the European (non-Finnish) subpopulation. The c.[298T>A;700G>C;824G>A] (p.[W100R;V234L;G275D]) haplotype was previously reported homozygous or compound heterozygous with another alteration in THOC1 in multiple patients with Beaulieu–Boycott–Innes syndrome (Casey, 2016; Mattioli, 2019; Gupta, 2020). The patients were reported to have intellectual disability, varying dysmorphic features, and other congenital anomalies including cardiac, genitourinary, renal, and skeletal malformations. The p.W100, p.V234, and p.G275 amino acids are conserved in available vertebrate species. The p.W100R amino acid is located in a separate domain than the domains with the p.V234L and p.G275D amino acids and together may affect the functionality of the larger WD40 domain. Functional expression assays demonstrated that the triple mutant protein showed an abnormal cytosolic localization as compared to wild type which localizes to the nucleus. The mutant protein alters THOC6 physiological nuclear localization and disrupts its interaction with two other subunits of THO, THOC1 and THOC5. The assays show that the pathogenicity of the haplotype results from a combined effect of at least two of the three missense changes (Mattioli, 2019). The in silico prediction for the p.W100R and p.G275D alterations are inconclusive. The p.V234L alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as 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

- -

Dystonia, early-onset, and/or spastic paraplegia

Uncertain:1

May 16, 2019

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

Significance:Uncertain significance

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

0.039

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;.;T;T

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.74

D;D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.2

M;.;.;M

PhyloP100

6.7

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-9.8

D;.;.;D

REVEL

Uncertain

0.39

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.89

MutPred

0.57

Gain of disorder (P = 0.0357);.;.;Gain of disorder (P = 0.0357);

MVP

0.60

MPC

0.65

ClinPred

0.99

GERP RS

5.5

Varity_R

0.96

gMVP

0.92

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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