Genetic Variant THRAP3:p.Glu170Gln (chr1-36286738-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005119.4(THRAP3):c.508G>C(p.Glu170Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THRAP3
NM_005119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58

Variant links:

Genes affected

THRAP3 (HGNC:22964): (thyroid hormone receptor associated protein 3) Enables phosphoprotein binding activity; thyroid hormone receptor binding activity; and transcription coactivator activity. Involved in nuclear-transcribed mRNA catabolic process; positive regulation of circadian rhythm; and regulation of RNA metabolic process. Acts upstream of or within positive regulation of transcription by RNA polymerase II. Located in nuclear speck. Part of mediator complex. Colocalizes with exon-exon junction complex. [provided by Alliance of Genome Resources, Apr 2022]

THRAP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2597198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRAP3	NM_005119.4 link	c.508G>C	p.Glu170Gln	missense_variant	Exon 4 of 12	ENST00000354618.10	NP_005110.2	Q9Y2W1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THRAP3	ENST00000354618.10 link	c.508G>C	p.Glu170Gln	missense_variant	Exon 4 of 12	1	NM_005119.4	ENSP00000346634.5	Q9Y2W1
THRAP3	ENST00000469141.6 link	c.508G>C	p.Glu170Gln	missense_variant	Exon 5 of 13	1		ENSP00000433825.1	Q9Y2W1
THRAP3	ENST00000648638.1 link	c.508G>C	p.Glu170Gln	missense_variant	Exon 5 of 14			ENSP00000498001.1	A0A3B3ITZ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.508G>C (p.E170Q) alteration is located in exon 4 (coding exon 2) of the THRAP3 gene. This alteration results from a G to C substitution at nucleotide position 508, causing the glutamic acid (E) at amino acid position 170 to be replaced by a glutamine (Q). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.0062

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.

PhyloP100

6.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.31

N;N;.

REVEL

Benign

0.090

Sift

Uncertain

0.0030

D;D;.

Sift4G

Benign

0.27

T;T;.

Polyphen

0.43

B;B;.

Vest4

0.28

MutPred

0.25

Loss of methylation at R168 (P = 0.2346);Loss of methylation at R168 (P = 0.2346);Loss of methylation at R168 (P = 0.2346);

MVP

0.23

MPC

0.43

ClinPred

0.75

GERP RS

5.7

Varity_R

0.29

gMVP

0.46

Mutation Taster

=85/15

polymorphism

(source)

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.

chr1-36286738-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over