rs1049534

Variant names:

• chr22-29512083-C-T
• rs1049534
• NM_003678.5:c.1735G>A
• THOC5 p.Val579Ile

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003678.5(THOC5):​c.1735G>A​(p.Val579Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,602 control chromosomes in the GnomAD database, including 43,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V579F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3350 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40086 hom.)
• Consequence: THOC5 NM_003678.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303
• Publications: 36 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3370981E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

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.1735G>A	p.Val579Ile	missense	Exon 18 of 20	NP_003669.4
	THOC5	NM_001002877.2		c.1735G>A	p.Val579Ile	missense	Exon 19 of 21	NP_001002877.1	Q13769
	THOC5	NM_001002878.1		c.1735G>A	p.Val579Ile	missense	Exon 19 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.1735G>A	p.Val579Ile	missense	Exon 18 of 20	ENSP00000420306.1	Q13769
	THOC5	ENST00000853420.1		c.1885G>A	p.Val629Ile	missense	Exon 19 of 21	ENSP00000523479.1
	THOC5	ENST00000928658.1		c.1789G>A	p.Val597Ile	missense	Exon 20 of 22	ENSP00000598717.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30190 AN: 152032 Hom.: 3353 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.222 AC: 55746 AN: 251172 AF XY: 0.223

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.228 AC: 333787 AN: 1461450 Hom.: 40086 Cov.: 33 AF XY: 0.227 AC XY: 165020 AN XY: 727004

African (AFR) AF: 0.123 AC: 4109 AN: 33478

American (AMR) AF: 0.188 AC: 8390 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6822 AN: 26124

East Asian (EAS) AF: 0.466 AC: 18465 AN: 39654

South Asian (SAS) AF: 0.182 AC: 15726 AN: 86230

European-Finnish (FIN) AF: 0.197 AC: 10520 AN: 53414

Middle Eastern (MID) AF: 0.257 AC: 1476 AN: 5754

European-Non Finnish (NFE) AF: 0.229 AC: 254206 AN: 1111712

Other (OTH) AF: 0.233 AC: 14073 AN: 60374

GnomAD4 genome AF: 0.198 AC: 30193 AN: 152152 Hom.: 3350 Cov.: 32 AF XY: 0.196 AC XY: 14615 AN XY: 74382

African (AFR) AF: 0.118 AC: 4896 AN: 41520

American (AMR) AF: 0.209 AC: 3201 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 954 AN: 3470

East Asian (EAS) AF: 0.431 AC: 2225 AN: 5168

South Asian (SAS) AF: 0.189 AC: 912 AN: 4826

European-Finnish (FIN) AF: 0.188 AC: 1985 AN: 10580

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15307 AN: 67990

Other (OTH) AF: 0.223 AC: 471 AN: 2112

Alfa AF: 0.223 Hom.: 10434

Bravo AF: 0.202

Asia WGS AF: 0.273 AC: 950 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.236

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.0
DANN	Benign	0.73
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.00023	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.32	N
PhyloP100		-0.30
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.045
Sift	Benign	0.98	T
Sift4G	Benign	0.63	T
Varity_R		0.012
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1049534;

hg19: chr22-29908072;

COSMIC: COSV63797673;

COSMIC: COSV63797673;