X-123621193-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001081550.2(THOC2):c.4180C>T(p.Pro1394Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: THOC2 NM_001081550.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

THOC2 (HGNC:19073): (THO complex subunit 2) The TREX multiprotein complex binds specifically to spliced mRNAs to facilitate mRNA export. The protein encoded by this gene is a member of the THO complex, a subset of the TREX complex. The encoded protein interacts with the THOC1 protein.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, THOC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.21672773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC2	NM_001081550.2	c.4180C>T	p.Pro1394Ser	missense_variant	31/39	ENST00000245838.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC2	ENST00000245838.13	c.4180C>T	p.Pro1394Ser	missense_variant	31/39	5	NM_001081550.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000569 AC: 1 AN: 175896 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 62736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000758

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.4180C>T (p.P1394S) alteration is located in exon 31 (coding exon 31) of the THOC2 gene. This alteration results from a C to T substitution at nucleotide position 4180, causing the proline (P) at amino acid position 1394 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.;T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N;.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Benign	0.074
Sift	Benign	0.086	T;.;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.98	D;.;D;.
Vest4		0.25
MutPred		0.24		Gain of phosphorylation at P1394 (P = 0.0022);.;Gain of phosphorylation at P1394 (P = 0.0022);.;
MVP		0.31
MPC		0.80
ClinPred		0.37	T
GERP RS		5.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.21
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs780690081; hg19: chrX-122755044;