rs138632121

chr16-3026140-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

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 Likely 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:8
• Conservation: PhyloP100: 6.68

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3026140-T-A is Pathogenic according to our data. Variant chr16-3026140-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3026140-T-A is described in Lovd as [Pathogenic]. Variant chr16-3026140-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC6	NM_024339.5	c.298T>A	p.Trp100Arg	missense_variant	4/13	ENST00000326266.13
THOC6	NM_001347704.2	c.298T>A	p.Trp100Arg	missense_variant	5/14
THOC6	NM_001347703.2	c.226T>A	p.Trp76Arg	missense_variant	5/14
THOC6	NM_001142350.3	c.298T>A	p.Trp100Arg	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC6	ENST00000326266.13	c.298T>A	p.Trp100Arg	missense_variant	4/13	1	NM_024339.5	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152176 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000173 AC: 43 AN: 248640 Hom.: 0 AF XY: 0.000209 AC XY: 28 AN XY: 134288

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 SAS exome AF: 0.0000332

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.: 0 Cov.: 38 AF XY: 0.000359 AC XY: 260 AN XY: 723386

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000463

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74476

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000373 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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	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. -
Pathogenic, criteria provided, single submitter	research	Medgenome Labs Pvt Ltd	Feb 02, 2019	- -
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 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 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 abnormal protein localization (PMID: 30476144). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 21, 2022	- -

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 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) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
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	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs138632121; hg19: chr16-3076141;