16-3026166-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024339.5(THOC6):c.324G>C(p.Lys108Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: THOC6 NM_024339.5 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.28

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC6	NM_024339.5	c.324G>C	p.Lys108Asn	missense_variant, splice_region_variant	4/13	ENST00000326266.13
THOC6	NM_001347704.2	c.324G>C	p.Lys108Asn	missense_variant, splice_region_variant	5/14
THOC6	NM_001347703.2	c.252G>C	p.Lys84Asn	missense_variant, splice_region_variant	5/14
THOC6	NM_001142350.3	c.324G>C	p.Lys108Asn	missense_variant, splice_region_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC6	ENST00000326266.13	c.324G>C	p.Lys108Asn	missense_variant, splice_region_variant	4/13	1	NM_024339.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 17, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.043	T;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;.;T;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.2	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;.;.;N
REVEL	Benign	0.21
Sift4G	Uncertain	0.036	D;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.62
MutPred		0.42		Loss of glycosylation at K108 (P = 0.0359);.;.;Loss of glycosylation at K108 (P = 0.0359);
MVP		0.79
MPC		0.51
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1302083979; hg19: chr16-3076167;