dbSNP rs1556302160: THOC2:p.Arg77Cys (chrX-123703499-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_001081550.2(THOC2):c.229C>T(p.Arg77Cys) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

THOC2
NM_001081550.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 4.35

Variant links:

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]

THOC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the THOC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 5.5258 (above the threshold of 3.09). GenCC associations: The gene is linked to X-linked intellectual disability-short stature-overweight syndrome.

PP5

Variant X-123703499-G-A is Pathogenic according to our data. Variant chrX-123703499-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488436.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}. Variant chrX-123703499-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC2	NM_001081550.2 link	c.229C>T	p.Arg77Cys	missense_variant	Exon 4 of 39	ENST00000245838.13	NP_001075019.1	Q8NI27-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THOC2	ENST00000245838.13 link	c.229C>T	p.Arg77Cys	missense_variant	Exon 4 of 39	5	NM_001081550.2	ENSP00000245838.8	Q8NI27-1
THOC2	ENST00000355725.8 link	c.229C>T	p.Arg77Cys	missense_variant	Exon 4 of 39	5		ENSP00000347959.4	Q8NI27-1
THOC2	ENST00000419789.1 link	n.158C>T		non_coding_transcript_exon_variant	Exon 3 of 4	5
THOC2	ENST00000433883.1 link	n.229C>T		non_coding_transcript_exon_variant	Exon 4 of 10	5		ENSP00000415374.1	F2Z2V2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1044323

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

319199

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked intellectual disability-short stature-overweight syndrome

Pathogenic:2Uncertain:2

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

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 Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with THOC2-related neurodevelopmental disorder (MIM#300957). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in three individuals with THOC2-related neurodevelopmental disorder, two of them de novo (PMID: 32960281, 29851191, 32116545). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on patient cells showed reduced protein levels (PMID: 32116545). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 02, 2018

Sydney Children's Hospital, SCHN

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 16, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 05, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Apr 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32116545, 32960281) -

Inborn genetic diseases

Uncertain:1

Mar 23, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.27

Sift

Benign

0.11

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.57

P;P

Vest4

0.47

MutPred

0.47

Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);

MVP

0.74

MPC

1.5

ClinPred

0.97

GERP RS

5.1

Varity_R

0.30

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: 6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over