5-175965059-C-A

Variant names:

• chr5-175965059-C-A
• NM_032361.4:c.521G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032361.4(THOC3):​c.521G>T​(p.Arg174Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: THOC3 NM_032361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC3	NM_032361.4	c.521G>T	p.Arg174Leu	missense_variant	Exon 3 of 6	ENST00000265097.9	NP_115737.1
THOC3	NM_001376902.1	c.521G>T	p.Arg174Leu	missense_variant	Exon 3 of 5		NP_001363831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC3	ENST00000265097.9	c.521G>T	p.Arg174Leu	missense_variant	Exon 3 of 6	1	NM_032361.4	ENSP00000265097.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.521G>T (p.R174L) alteration is located in exon 3 (coding exon 3) of the THOC3 gene. This alteration results from a G to T substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a leucine (L). 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	0.62
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	0.058
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.20
Sift	Benign	0.039	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	B;.
Vest4		0.72
MutPred		0.50		Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);
MVP		0.34
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-175392062;