rs200426926

chr16-3027379-G-Achr16-3027379-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ACMG classification

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: 31 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000176 AC: 44 AN: 249820 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135282

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000381 AC: 556 AN: 1460488 Hom.: 0 Cov.: 38 AF XY: 0.000358 AC XY: 260 AN XY: 726406

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000462

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152388 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74518

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome Pathogenic:6

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. -
Pathogenic, criteria provided, single submitter	research	Medgenome Labs Pvt Ltd	Feb 02, 2019	- -
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	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	May 06, 2021	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 patients with intellectual disability (PMID: 30476144, 31421288, 27295358). (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 -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.9	D;.;.
REVEL	Uncertain	0.37
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.64	P;.;.
Vest4		0.79
MVP		0.49
MPC		0.56
ClinPred		0.96	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs200426926; hg19: chr16-3077380;