rs200426926
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_024339.5(THOC6):c.824G>A(p.Gly275Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000364 in 1,612,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275A) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00038 ( 0 hom. )
Consequence
THOC6
NM_024339.5 missense
NM_024339.5 missense
Scores
2
11
5
Clinical Significance
Conservation
PhyloP100: 4.15
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a repeat WD 6 (size 37) in uniprot entity THOC6_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_024339.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr16-3027379-G-C is described in Lovd as [Pathogenic].
PP5
?
Variant 16-3027379-G-A is Pathogenic according to our data. Variant chr16-3027379-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3027379-G-A is described in Lovd as [Pathogenic]. Variant chr16-3027379-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THOC6 | NM_024339.5 | c.824G>A | p.Gly275Asp | missense_variant | 12/13 | ENST00000326266.13 | |
THOC6 | NM_001347704.2 | c.824G>A | p.Gly275Asp | missense_variant | 13/14 | ||
THOC6 | NM_001347703.2 | c.752G>A | p.Gly251Asp | missense_variant | 13/14 | ||
THOC6 | NM_001142350.3 | c.810+99G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THOC6 | ENST00000326266.13 | c.824G>A | p.Gly275Asp | missense_variant | 12/13 | 1 | NM_024339.5 | P1 | |
THOC6 | ENST00000574549.5 | c.752G>A | p.Gly251Asp | missense_variant | 13/14 | 1 | |||
THOC6 | ENST00000575576.5 | c.752G>A | p.Gly251Asp | missense_variant | 12/13 | 5 | |||
THOC6 | ENST00000253952.9 | c.810+99G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152270Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
31
AN:
152270
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000176 AC: 44AN: 249820Hom.: 0 AF XY: 0.000207 AC XY: 28AN XY: 135282
GnomAD3 exomes
AF:
AC:
44
AN:
249820
Hom.:
AF XY:
AC XY:
28
AN XY:
135282
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000381 AC: 556AN: 1460488Hom.: 0 Cov.: 38 AF XY: 0.000358 AC XY: 260AN XY: 726406
GnomAD4 exome
AF:
AC:
556
AN:
1460488
Hom.:
Cov.:
38
AF XY:
AC XY:
260
AN XY:
726406
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000203 AC: 31AN: 152388Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74518
GnomAD4 genome
?
AF:
AC:
31
AN:
152388
Hom.:
Cov.:
33
AF XY:
AC XY:
16
AN XY:
74518
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
2
ALSPAC
AF:
AC:
2
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
4
ExAC
?
AF:
AC:
27
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | research | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Pathogenic, criteria provided, single submitter | research | Medgenome Labs Pvt Ltd | Feb 02, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 21, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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 glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (49 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) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated WD6 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 impaired THOC1/5 interactions (PMID: 30476144). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | The missense c.824G>A(p.Gly275Asp) variant in THOC6 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 submission). The amino acid change p.Gly275Asp in THOC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 275 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2020 | 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 G275D variant on its own was also suggested to decrease interaction with protein partners (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: 31216405, 31421288, 30476144, 27295358, 26739162, 20503307, 23621916, 27102954, 15998806, 19059247, 11060033) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2021 | The c.824G>A (p.G275D) alteration is located in coding exon 12 of the THOC6 gene. This alteration results from 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) database, the THOC6 c.824G>A alteration was observed in 0.02% (49/281,212) of total alleles studied, with a frequency of 0.03% (36/128,392) in the European (non-Finnish) subpopulation. The c.298T>A (p.W100R), c.700G>C (p.V234L), and c.824G>A (p.G275D) alterations make up a known haplotype which 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.G275 amino acid is conserved in available vertebrate species. The p.G275D amino acid is located in a separate domain than the domains with the p.W100R and p.V234L amino acids and together may affect the functionality of the larger WD40 domain. Functional expression assays demonstrated that the c.(298T>A; 700G>C; 824G>C) haplotype in THOC6 alters THOC6 physiological nuclear localization and its interaction with other members of the THO complex, THOC1 and THOC5 and 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.G275D alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.
REVEL
Uncertain
Sift4G
Uncertain
D;D;D
Polyphen
P;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at