rs367977934

Variant names:

• chr5-175965021-C-T
• rs367977934
• NM_032361.4:c.559G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032361.4(THOC3):​c.559G>A​(p.Glu187Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000863 in 1,505,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: THOC3 NM_032361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

Genes affected

THOC3 (HGNC:19072): (THO complex subunit 3) This gene encodes a component of the nuclear THO transcription elongation complex, which is part of the larger transcription export (TREX) complex that couples messenger RNA processing and export. In humans, the transcription export complex is recruited to the 5'-end of messenger RNAs in a splicing- and cap-dependent manner. Studies of a related complex in mouse suggest that the metazoan transcription export complex is involved in cell differentiation and development. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032361.4. 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
	THOC3	NM_032361.4	MANE Select	c.559G>A	p.Glu187Lys	missense	Exon 3 of 6	NP_115737.1	Q96J01-1
	THOC3	NM_001376902.1		c.559G>A	p.Glu187Lys	missense	Exon 3 of 5	NP_001363831.1	Q96J01-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC3	ENST00000265097.9	TSL:1 MANE Select	c.559G>A	p.Glu187Lys	missense	Exon 3 of 6	ENSP00000265097.5	Q96J01-1
	THOC3	ENST00000513482.1	TSL:1	c.559G>A	p.Glu187Lys	missense	Exon 3 of 5	ENSP00000422243.1	Q96J01-2
	THOC3	ENST00000928778.1		c.559G>A	p.Glu187Lys	missense	Exon 3 of 6	ENSP00000598837.1

Frequencies

GnomAD3 genomes AF: 0.0000278 AC: 4 AN: 144086 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000857 AC: 2 AN: 233352 AF XY: 0.00

Gnomad AFR exome AF: 0.0000667

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000661 AC: 9 AN: 1361870 Hom.: 0 Cov.: 25 AF XY: 0.00000442 AC XY: 3 AN XY: 679192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000641 AC: 2 AN: 31210

American (AMR) AF: 0.00 AC: 0 AN: 42848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24486

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.0000487 AC: 4 AN: 82060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.00000292 AC: 3 AN: 1027078

Other (OTH) AF: 0.00 AC: 0 AN: 56818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000236720), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000278 AC: 4 AN: 144086 Hom.: 0 Cov.: 23 AF XY: 0.0000143 AC XY: 1 AN XY: 69750

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000105 AC: 4 AN: 38116

American (AMR) AF: 0.00 AC: 0 AN: 14292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5036

South Asian (SAS) AF: 0.00 AC: 0 AN: 4346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66110

Other (OTH) AF: 0.00 AC: 0 AN: 1938

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00215951), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.097	T
Polyphen		0.99	D
Vest4		0.89
MVP		0.39
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.77
gMVP		0.71
Mutation Taster		=47/53	disease causing

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: rs367977934; hg19: chr5-175392024; COSMIC: COSV99442237; COSMIC: COSV99442237;