chr22-29512122-C-A

Variant names:

• chr22-29512122-C-A
• rs779657865
• NM_003678.5:c.1696G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003678.5(THOC5):​c.1696G>T​(p.Ala566Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: THOC5 NM_003678.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39156783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC5	NM_003678.5	c.1696G>T	p.Ala566Ser	missense_variant	Exon 18 of 20	ENST00000490103.6	NP_003669.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC5	ENST00000490103.6	c.1696G>T	p.Ala566Ser	missense_variant	Exon 18 of 20	1	NM_003678.5	ENSP00000420306.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1696G>T (p.A566S) alteration is located in exon 19 (coding exon 17) of the THOC5 gene. This alteration results from a G to T substitution at nucleotide position 1696, causing the alanine (A) at amino acid position 566 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	Benign	0.20
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;.;D;.
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.95	P;P;P;P
Vest4		0.50
MutPred		0.47		Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);
MVP		0.33
MPC		0.35
ClinPred		0.81	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs779657865; hg19: chr22-29908111;