Variant 19-2790624-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003249.5(THOP1):c.220A>G(p.Thr74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,408,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

THOP1
NM_003249.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09

Variant links:

Genes affected

THOP1 (HGNC:11793): (thimet oligopeptidase 1) The protein encoded by this gene is a kininase that uses zinc as a cofactor. The encoded oligopeptidase cleaves cytosolic peptides, making them unavailable for display on antigen-presenting cells. This protein also cleaves neuropeptides under 20 aa in length and can degrade beta-amyloid precursor protein to amyloidogenic peptides. [provided by RefSeq, Nov 2015]

THOP1 links:

THOP1 (HGNC:):

THOP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12677199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THOP1	NM_003249.5 linkuse as main transcript	c.220A>G	p.Thr74Ala	missense_variant	2/13	ENST00000307741.11	NP_003240.1	P52888-1
THOP1	XM_047439299.1 linkuse as main transcript	c.220A>G	p.Thr74Ala	missense_variant	2/10		XP_047295255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
THOP1	ENST00000307741.11 linkuse as main transcript	c.220A>G	p.Thr74Ala	missense_variant	2/13	1	NM_003249.5	ENSP00000304467.5	P52888-1
THOP1	ENST00000585338.1 linkuse as main transcript	c.190A>G	p.Thr64Ala	missense_variant	3/6	3		ENSP00000465545.1	K7EKB6
THOP1	ENST00000585673.5 linkuse as main transcript	n.369A>G		non_coding_transcript_exon_variant	2/6	3
THOP1	ENST00000586780.1 linkuse as main transcript	n.316A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000497

AC:

AN:

1408932

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

696922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000552

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.220A>G (p.T74A) alteration is located in exon 2 (coding exon 2) of the THOP1 gene. This alteration results from a A to G substitution at nucleotide position 220, causing the threonine (T) at amino acid position 74 to be replaced by an alanine (A). 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

Benign

0.063

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.086

T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.065

N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.93

N;.

REVEL

Benign

0.071

Sift

Benign

0.41

T;.

Sift4G

Benign

0.51

T;T

Polyphen

0.0

B;.

Vest4

0.075

MutPred

0.36

Loss of catalytic residue at E72 (P = 0.2064);.;

MVP

0.14

MPC

0.24

ClinPred

0.080

GERP RS

-3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.042

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over