19-2799777-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003249.5(THOP1):​c.575C>T​(p.Thr192Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

THOP1
NM_003249.5 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.68
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28982723).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
THOP1NM_003249.5 linkc.575C>T p.Thr192Met missense_variant 5/13 ENST00000307741.11 NP_003240.1 P52888-1
THOP1XM_047439299.1 linkc.575C>T p.Thr192Met missense_variant 5/10 XP_047295255.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
THOP1ENST00000307741.11 linkc.575C>T p.Thr192Met missense_variant 5/131 NM_003249.5 ENSP00000304467.5 P52888-1
THOP1ENST00000586677.5 linkc.212C>T p.Thr71Met missense_variant 2/102 ENSP00000467226.1 K7EP46
THOP1ENST00000585673.5 linkn.724C>T non_coding_transcript_exon_variant 5/63
THOP1ENST00000585338.1 linkc.*15C>T downstream_gene_variant 3 ENSP00000465545.1 K7EKB6

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152270
Hom.:
0
Cov.:
33
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250954
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135664
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461358
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726968
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152270
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74392
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsDec 03, 2024The c.575C>T (p.T192M) alteration is located in exon 5 (coding exon 5) of the THOP1 gene. This alteration results from a C to T substitution at nucleotide position 575, causing the threonine (T) at amino acid position 192 to be replaced by a methionine (M). 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
0.17
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.26
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.68
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.29
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-3.7
D;.
REVEL
Benign
0.13
Sift
Uncertain
0.011
D;.
Sift4G
Uncertain
0.0020
D;D
Polyphen
0.99
D;.
Vest4
0.38
MutPred
0.27
Loss of sheet (P = 0.0457);.;
MVP
0.36
MPC
0.46
ClinPred
0.91
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.071
gMVP
0.76

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.

Other links and lift over

dbSNP: rs772371484; hg19: chr19-2799775; COSMIC: COSV57019253; COSMIC: COSV57019253; API