rs138632121

Variant names:

• chr16-3026140-T-A
• rs138632121
• NM_024339.5:c.298T>A
• THOC6 p.Trp100Arg

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV000741882: 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)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: THOC6 NM_024339.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 6.68
• Publications: 11 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000741882: 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).; SCV002768132: "Functional studies show that this variant causes abnormal protein localization." PMID:30476144; SCV004175800: experimental evidence shows that this variants affects the physiological nuclear localizationof the THOC6 protein (Mattioli F, et al., 2019; Gupta N, et al., 2020).; SCV005900720: 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).; SCV001823021: 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)
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	NM_024339.5	MANE Select	c.298T>A	p.Trp100Arg	missense	Exon 4 of 13	NP_077315.2
	THOC6	NM_001347704.2		c.298T>A	p.Trp100Arg	missense	Exon 5 of 14	NP_001334633.1	Q86W42-1
	THOC6	NM_001347703.2		c.226T>A	p.Trp76Arg	missense	Exon 5 of 14	NP_001334632.1	Q86W42-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	ENST00000326266.13	TSL:1 MANE Select	c.298T>A	p.Trp100Arg	missense	Exon 4 of 13	ENSP00000326531.8	Q86W42-1
	THOC6	ENST00000574549.5	TSL:1	c.226T>A	p.Trp76Arg	missense	Exon 5 of 14	ENSP00000458295.1	Q86W42-2
	THOC6	ENST00000571057.5	TSL:1	n.756T>A		non_coding_transcript_exon	Exon 2 of 4

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

GnomAD2 exomes AF: 0.000173 AC: 43 AN: 248640 AF XY: 0.000209

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

African (AFR) AF: 0.0000601 AC: 2 AN: 33292

American (AMR) AF: 0.0000225 AC: 1 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25816

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39572

South Asian (SAS) AF: 0.000198 AC: 17 AN: 85876

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000463 AC: 513 AN: 1107940

Other (OTH) AF: 0.000200 AC: 12 AN: 60090

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000373 Hom.: 0

Bravo AF: 0.000162

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	-	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome (6)
2	-	-	not provided (2)
-	1	-	Dystonia, early-onset, and/or spastic paraplegia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-9.8	D
REVEL	Uncertain	0.39
Sift4G	Pathogenic	0.0	D
Varity_R		0.96
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs138632121; hg19: chr16-3076141;