22-29517289-C-T

Variant names:

• chr22-29517289-C-T
• rs35832657
• NM_003678.5:c.1567G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003678.5(THOC5):​c.1567G>A​(p.Val523Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,614,190 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (84 hom.)
• Consequence: THOC5 NM_003678.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14
• Publications: 6 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003942013).
• BP6: Variant 22-29517289-C-T is Benign according to our data. Variant chr22-29517289-C-T is described in ClinVar as Benign. ClinVar VariationId is 782635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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.1567G>A	p.Val523Met	missense	Exon 16 of 20	NP_003669.4
	THOC5	NM_001002877.2		c.1567G>A	p.Val523Met	missense	Exon 17 of 21	NP_001002877.1	Q13769
	THOC5	NM_001002878.1		c.1567G>A	p.Val523Met	missense	Exon 17 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.1567G>A	p.Val523Met	missense	Exon 16 of 20	ENSP00000420306.1	Q13769
	THOC5	ENST00000853420.1		c.1717G>A	p.Val573Met	missense	Exon 17 of 21	ENSP00000523479.1
	THOC5	ENST00000928658.1		c.1621G>A	p.Val541Met	missense	Exon 18 of 22	ENSP00000598717.1

Frequencies

GnomAD3 genomes AF: 0.00759 AC: 1156 AN: 152208 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00848 AC: 2132 AN: 251388 AF XY: 0.00827

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.00720

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00572 AC: 8369 AN: 1461864 Hom.: 84 Cov.: 33 AF XY: 0.00594 AC XY: 4319 AN XY: 727232

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00334 AC: 288 AN: 86258

European-Finnish (FIN) AF: 0.0468 AC: 2501 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00471 AC: 5241 AN: 1111994

Other (OTH) AF: 0.00419 AC: 253 AN: 60396

GnomAD4 genome AF: 0.00760 AC: 1157 AN: 152326 Hom.: 18 Cov.: 33 AF XY: 0.00925 AC XY: 689 AN XY: 74488

African (AFR) AF: 0.000553 AC: 23 AN: 41578

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00781 AC: 531 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00634 Hom.: 19

Bravo AF: 0.00314

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00787 AC: 955

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.0062
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.019
Sift	Benign	0.15	T
Sift4G	Benign	0.13	T
Polyphen		0.51	P
Vest4		0.095
MVP		0.23
MPC		0.38
ClinPred		0.0096	T
GERP RS		3.2
Varity_R		0.047
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35832657; hg19: chr22-29913278; COSMIC: COSV99063786; COSMIC: COSV99063786;