rs1049534

chr22-29512083-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC5	NM_003678.5	c.1735G>A	p.Val579Ile	missense_variant	18/20	ENST00000490103.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC5	ENST00000490103.6	c.1735G>A	p.Val579Ile	missense_variant	18/20	1	NM_003678.5	P1

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

GnomAD3 exomes AF: 0.222 AC: 55746 AN: 251172 Hom.: 6791 AF XY: 0.223 AC XY: 30240 AN XY: 135748

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 SAS exome AF: 0.184

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

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.466

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.233

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

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.223

Alfa AF: 0.231 Hom.: 7687

Bravo AF: 0.202

TwinsUK AF: 0.214 AC: 795

ALSPAC AF: 0.230 AC: 887

ESP6500AA AF: 0.127 AC: 559

ESP6500EA AF: 0.228 AC: 1957

ExAC AF: 0.217 AC: 26378

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 v4.3

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;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	0.00023	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.32	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.40	N;N;N;N
REVEL	Benign	0.045
Sift	Benign	0.98	T;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.022
MPC		0.31
ClinPred		0.00030	T
GERP RS		1.1
Varity_R		0.012
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs1049534; hg19: chr22-29908072; COSMIC: COSV63797673; COSMIC: COSV63797673;