19-2790612-G-A

Variant summary

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

The NM_003249.5(THOP1):​c.208G>A​(p.Asp70Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,573,190 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 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

THOP1
NM_003249.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19687551).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
THOP1NM_003249.5 linkc.208G>A p.Asp70Asn missense_variant 2/13 ENST00000307741.11 NP_003240.1 P52888-1
THOP1XM_047439299.1 linkc.208G>A p.Asp70Asn missense_variant 2/10 XP_047295255.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
THOP1ENST00000307741.11 linkc.208G>A p.Asp70Asn missense_variant 2/131 NM_003249.5 ENSP00000304467.5 P52888-1
THOP1ENST00000585338.1 linkc.178G>A p.Asp60Asn missense_variant 3/63 ENSP00000465545.1 K7EKB6
THOP1ENST00000585673.5 linkn.357G>A non_coding_transcript_exon_variant 2/63
THOP1ENST00000586780.1 linkn.304G>A non_coding_transcript_exon_variant 2/33

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000337
AC:
7
AN:
207998
Hom.:
0
AF XY:
0.0000179
AC XY:
2
AN XY:
111560
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000110
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000119
Gnomad SAS exome
AF:
0.0000460
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000104
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000373
AC:
53
AN:
1420972
Hom.:
0
Cov.:
31
AF XY:
0.0000327
AC XY:
23
AN XY:
704354
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000130
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000128
Gnomad4 SAS exome
AF:
0.0000381
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000357
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000651
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000577
AC:
7

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 GeneticsOct 25, 2022The c.208G>A (p.D70N) 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 208, causing the aspartic acid (D) at amino acid position 70 to be replaced by an asparagine (N). 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
0.11
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;T
Eigen
Benign
0.084
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.1
N;.
REVEL
Benign
0.13
Sift
Benign
0.17
T;.
Sift4G
Benign
0.28
T;T
Polyphen
0.46
P;.
Vest4
0.30
MVP
0.42
MPC
0.26
ClinPred
0.14
T
GERP RS
4.7
Varity_R
0.31
gMVP
0.59

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: rs149372415; hg19: chr19-2790610; COSMIC: COSV57017718; API