Variant 19-2790444-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000307741.11(THOP1):c.40G>A(p.Ala14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,571,534 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: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

THOP1
ENST00000307741.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.401

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033116788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THOP1	NM_003249.5 linkuse as main transcript	c.40G>A	p.Ala14Thr	missense_variant	2/13	ENST00000307741.11	NP_003240.1
THOP1	XM_047439299.1 linkuse as main transcript	c.40G>A	p.Ala14Thr	missense_variant	2/10		XP_047295255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THOP1	ENST00000307741.11 linkuse as main transcript	c.40G>A	p.Ala14Thr	missense_variant	2/13	1	NM_003249.5	ENSP00000304467	P1	P52888-1
THOP1	ENST00000585338.1 linkuse as main transcript	c.10G>A	p.Ala4Thr	missense_variant	3/6	3		ENSP00000465545
THOP1	ENST00000585673.5 linkuse as main transcript	n.189G>A		non_coding_transcript_exon_variant	2/6	3
THOP1	ENST00000586780.1 linkuse as main transcript	n.136G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000917

AC:

AN:

218040

Hom.:

AF XY:

0.00000851

AC XY:

AN XY:

117564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000102

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1419302

Hom.:

Cov.:

AF XY:

0.0000157

AC XY:

AN XY:

702746

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000248

Gnomad4 FIN exome

AF:

0.000154

Gnomad4 NFE exome

AF:

0.0000165

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

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

Jul 12, 2022

The c.40G>A (p.A14T) alteration is located in exon 2 (coding exon 2) of the THOP1 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the alanine (A) at amino acid position 14 to be replaced by a threonine (T). 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

0.070

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.45

DANN

Benign

0.59

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

PROVEAN

Benign

0.13

N;.

REVEL

Benign

0.019

Sift

Benign

0.49

T;.

Sift4G

Benign

0.80

T;T

Polyphen

0.0

B;.

Vest4

0.068

MVP

0.040

MPC

0.23

ClinPred

0.032

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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