22-29517035-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003678.5(THOC5):​c.1675G>A​(p.Gly559Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

THOC5
NM_003678.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66
Variant links:
Genes affected
THOC5 (HGNC:19074): (THO complex subunit 5) Predicted to enable mRNA binding activity. Involved in several processes, including monocyte differentiation; negative regulation of DNA damage checkpoint; and viral mRNA export from host cell nucleus. Located in nucleoplasm. Part of THO complex part of transcription export complex. Colocalizes with chromosome, telomeric region. Implicated in breast carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
THOC5NM_003678.5 linkc.1675G>A p.Gly559Ser missense_variant Exon 17 of 20 ENST00000490103.6 NP_003669.4 Q13769A0A024R1D6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
THOC5ENST00000490103.6 linkc.1675G>A p.Gly559Ser missense_variant Exon 17 of 20 1 NM_003678.5 ENSP00000420306.1 Q13769

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1675G>A (p.G559S) alteration is located in exon 18 (coding exon 16) of the THOC5 gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the glycine (G) at amino acid position 559 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
Pathogenic
0.67
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T;T;T;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;.;D;.
M_CAP
Benign
0.021
T
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.4
M;M;M;M
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.9
D;D;D;D
REVEL
Uncertain
0.39
Sift
Uncertain
0.014
D;D;D;D
Sift4G
Uncertain
0.019
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.84
MutPred
0.91
Gain of glycosylation at G559 (P = 0.1046);Gain of glycosylation at G559 (P = 0.1046);Gain of glycosylation at G559 (P = 0.1046);Gain of glycosylation at G559 (P = 0.1046);
MVP
0.59
MPC
1.1
ClinPred
0.97
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.44
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29913024; API