rs150940923

chr16-3027170-G-Achr16-3027170-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_024339.5(THOC6):c.700G>A(p.Val234Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V234L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THOC6 NM_024339.5 missense, splice_region
• Scores: Splicing: ADA: 0.5516
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3027170-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521348.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29686671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC6	NM_024339.5	c.700G>A	p.Val234Ile	missense_variant, splice_region_variant	11/13	ENST00000326266.13
THOC6	NM_001347704.2	c.700G>A	p.Val234Ile	missense_variant, splice_region_variant	12/14
THOC6	NM_001347703.2	c.628G>A	p.Val210Ile	missense_variant, splice_region_variant	12/14
THOC6	NM_001142350.3	c.700G>A	p.Val234Ile	missense_variant, splice_region_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC6	ENST00000326266.13	c.700G>A	p.Val234Ile	missense_variant, splice_region_variant	11/13	1	NM_024339.5	P1
THOC6	ENST00000574549.5	c.628G>A	p.Val210Ile	missense_variant, splice_region_variant	12/14	1
THOC6	ENST00000575576.5	c.628G>A	p.Val210Ile	missense_variant, splice_region_variant	11/13	5
THOC6	ENST00000253952.9	c.700G>A	p.Val234Ile	missense_variant, splice_region_variant	11/12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;L
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.41	N;.;.;N
REVEL	Benign	0.099
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.69	P;.;.;B
Vest4		0.36
MutPred		0.37		Loss of sheet (P = 0.1501);.;.;Loss of sheet (P = 0.1501);
MVP		0.36
MPC		0.085
ClinPred		0.46	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.55
dbscSNV1_RF	Benign	0.53
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: rs150940923; hg19: chr16-3077171;