rs367977934

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032361.4(THOC3):​c.559G>A​(p.Glu187Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000863 in 1,505,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 23)
Exomes 𝑓: 0.0000066 ( 0 hom. )

Consequence

THOC3
NM_032361.4 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87
Variant links:
Genes affected
THOC3 (HGNC:19072): (THO complex subunit 3) This gene encodes a component of the nuclear THO transcription elongation complex, which is part of the larger transcription export (TREX) complex that couples messenger RNA processing and export. In humans, the transcription export complex is recruited to the 5'-end of messenger RNAs in a splicing- and cap-dependent manner. Studies of a related complex in mouse suggest that the metazoan transcription export complex is involved in cell differentiation and development. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
THOC3NM_032361.4 linkc.559G>A p.Glu187Lys missense_variant Exon 3 of 6 ENST00000265097.9 NP_115737.1 Q96J01-1
THOC3NM_001376902.1 linkc.559G>A p.Glu187Lys missense_variant Exon 3 of 5 NP_001363831.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
THOC3ENST00000265097.9 linkc.559G>A p.Glu187Lys missense_variant Exon 3 of 6 1 NM_032361.4 ENSP00000265097.5 Q96J01-1

Frequencies

GnomAD3 genomes
AF:
0.0000278
AC:
4
AN:
144086
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.000105
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000857
AC:
2
AN:
233352
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
126664
show subpopulations
Gnomad AFR exome
AF:
0.0000667
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000365
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000661
AC:
9
AN:
1361870
Hom.:
0
Cov.:
25
AF XY:
0.00000442
AC XY:
3
AN XY:
679192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000641
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000487
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000292
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000278
AC:
4
AN:
144086
Hom.:
0
Cov.:
23
AF XY:
0.0000143
AC XY:
1
AN XY:
69750
show subpopulations
Gnomad4 AFR
AF:
0.000105
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ESP6500AA
AF:
0.000230
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.559G>A (p.E187K) alteration is located in exon 3 (coding exon 3) of the THOC3 gene. This alteration results from a G to A substitution at nucleotide position 559, causing the glutamic acid (E) at amino acid position 187 to be replaced by a lysine (K). 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.15
T;.
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Benign
0.036
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.1
M;M
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-3.6
D;D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0020
D;D
Sift4G
Benign
0.097
T;T
Polyphen
0.99
D;.
Vest4
0.89
MVP
0.39
ClinPred
0.95
D
GERP RS
4.1
Varity_R
0.77
gMVP
0.71

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs367977934; hg19: chr5-175392024; COSMIC: COSV99442237; COSMIC: COSV99442237; API