chr22-29521007-T-C

Variant names:

• chr22-29521007-T-C
• NM_003678.5:c.1268A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003678.5(THOC5):​c.1268A>G​(p.Asp423Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THOC5 NM_003678.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50
• Publications: 0 publications found

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]

ENSG00000234208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003678.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC5	NM_003678.5	MANE Select	c.1268A>G	p.Asp423Gly	missense	Exon 13 of 20	NP_003669.4
	THOC5	NM_001002877.2		c.1268A>G	p.Asp423Gly	missense	Exon 14 of 21	NP_001002877.1	Q13769
	THOC5	NM_001002878.1		c.1268A>G	p.Asp423Gly	missense	Exon 14 of 21	NP_001002878.1	Q13769

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC5	ENST00000490103.6	TSL:1 MANE Select	c.1268A>G	p.Asp423Gly	missense	Exon 13 of 20	ENSP00000420306.1	Q13769
	THOC5	ENST00000853420.1		c.1418A>G	p.Asp473Gly	missense	Exon 14 of 21	ENSP00000523479.1
	THOC5	ENST00000928658.1		c.1322A>G	p.Asp441Gly	missense	Exon 15 of 22	ENSP00000598717.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.062	T
Sift4G	Benign	0.15	T
Polyphen		0.81	P
Vest4		0.73
MutPred		0.61		Loss of stability (P = 0.0145)
MVP		0.43
MPC		1.3
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.72
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 1

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

Other links and lift over

hg19: chr22-29916996;