16-3027170-G-C

Variant names:

• chr16-3027170-G-C
• rs150940923
• NM_024339.5:c.700G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024339.5(THOC6):​c.700G>C​(p.Val234Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000364 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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, splice_region
• Scores: Splicing: ADA: 0.5433
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 B:1
• Conservation: PhyloP100: 3.70
• Publications: 8 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09735671).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024339.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	NM_024339.5	MANE Select	c.700G>C	p.Val234Leu	missense splice_region	Exon 11 of 13	NP_077315.2
	THOC6	NM_001347704.2		c.700G>C	p.Val234Leu	missense splice_region	Exon 12 of 14	NP_001334633.1
	THOC6	NM_001347703.2		c.628G>C	p.Val210Leu	missense splice_region	Exon 12 of 14	NP_001334632.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	ENST00000326266.13	TSL:1 MANE Select	c.700G>C	p.Val234Leu	missense splice_region	Exon 11 of 13	ENSP00000326531.8
	THOC6	ENST00000574549.5	TSL:1	c.628G>C	p.Val210Leu	missense splice_region	Exon 12 of 14	ENSP00000458295.1
	THOC6	ENST00000575576.5	TSL:5	c.628G>C	p.Val210Leu	missense splice_region	Exon 11 of 13	ENSP00000460015.1

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251258 AF XY: 0.000206

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000380 AC: 556 AN: 1461838 Hom.: 0 Cov.: 38 AF XY: 0.000358 AC XY: 260 AN XY: 727216

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000462 AC: 514 AN: 1111996

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74456

African (AFR) AF: 0.0000963 AC: 4 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000338 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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome Pathogenic:1 Uncertain:2 Benign:1

Oct 21, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2019

Medgenome Labs Pvt Ltd

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

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 Benign. 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 valine to leucine. (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 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated WD5 repeat (PMID: 30476144). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has some previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as likely pathogenic, likely benign and as a VUS (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) 1010 - Functional evidence for this variant is inconclusive. Functional studies of this variant alone showed normal protein localization and THOC1/5 interactions (PMID: 30476144). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I)

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1 Uncertain:1

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 13, 2020

GeneDx

Significance: Uncertain significance

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, however, the V234L variant on its own did not affect nuclear localization nor interaction with protein partners (Mattioli et al., 2019); In silico analysis supports that this missense variant does not alter 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

Feb 22, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.700G>C (p.V234L) alteration is located in coding exon 11 of the THOC6 gene. This alteration results from 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). Based on data from the Genome Aggregation Database (gnomAD) database, the THOC6 c.700G>C alteration was observed in 0.02% (49/282,608) of total alleles studied, with a frequency of 0.03% (36/129,008) 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&ndash;Boycott&ndash;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.V234 amino acid is conserved in available vertebrate species. The p.V234L amino acid is located in a separate domain than the domains with the p.W100R and p.G275D 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 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.42	N
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.073
Sift4G	Benign	0.55	T
Polyphen		0.15	B
Vest4		0.19
MVP		0.40
MPC		0.098
ClinPred		0.61	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.45
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs150940923; hg19: chr16-3077171;