chr22-29519086-C-A

Position:

• chr22-29519086-C-A

Variant summary

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

The NM_003678.5(THOC5):​c.1409G>T​(p.Ser470Ile) 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: 7.67

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]

(HGNC:):

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/exons	MANE	UniProt
THOC5	NM_003678.5	c.1409G>T	p.Ser470Ile	missense_variant	15/20	ENST00000490103.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC5	ENST00000490103.6	c.1409G>T	p.Ser470Ile	missense_variant	15/20	1	NM_003678.5	P1
	ENST00000411969.1	n.162-5070G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.1409G>T (p.S470I) alteration is located in exon 16 (coding exon 14) of the THOC5 gene. This alteration results from a G to T substitution at nucleotide position 1409, causing the serine (S) at amino acid position 470 to be replaced by an isoleucine (I). 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	0.30
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.082	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.28	B;B;B;B
Vest4		0.87
MutPred		0.38		Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);Loss of disorder (P = 0.0011);
MVP		0.32
MPC		1.1
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.51

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: chr22-29915075;