GeneBe

NM_001330701.2:c.2736delC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001330701.2(AGTPBP1):​c.2736delC​(p.Tyr912fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,610,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AGTPBP1
NM_001330701.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -0.780

Publications

1 publications found
Variant links:
Genes affected
AGTPBP1 (HGNC:17258): (ATP/GTP binding carboxypeptidase 1) NNA1 is a zinc carboxypeptidase that contains nuclear localization signals and an ATP/GTP-binding motif that was initially cloned from regenerating spinal cord neurons of the mouse.[supplied by OMIM, Jul 2002]
AGTPBP1 Gene-Disease associations (from GenCC):
  • neurodegeneration, childhood-onset, with cerebellar atrophy
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • pontocerebellar hypoplasia type 1
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-85588464-CG-C is Pathogenic according to our data. Variant chr9-85588464-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 522817.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330701.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
AGTPBP1
NM_001330701.2
MANE Select
c.2736delCp.Tyr912fs
frameshift
Exon 21 of 26NP_001317630.1
AGTPBP1
NM_001286715.1
c.2892delCp.Tyr964fs
frameshift
Exon 20 of 25NP_001273644.1
AGTPBP1
NM_001286717.1
c.2772delCp.Tyr924fs
frameshift
Exon 20 of 25NP_001273646.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
AGTPBP1
ENST00000357081.8
TSL:5 MANE Select
c.2736delCp.Tyr912fs
frameshift
Exon 21 of 26ENSP00000349592.3
AGTPBP1
ENST00000376083.7
TSL:1
c.2616delCp.Tyr872fs
frameshift
Exon 21 of 26ENSP00000365251.3
AGTPBP1
ENST00000337006.8
TSL:5
c.2892delCp.Tyr964fs
frameshift
Exon 20 of 25ENSP00000338512.5

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152016
Hom.:
0
Cov.:
32
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
GnomAD2 exomes
AF:
0.00000404
AC:
1
AN:
247630
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458404
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725482
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33246
American (AMR)
AF:
0.00
AC:
0
AN:
43850
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26022
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39542
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85598
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53372
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1110742
Other (OTH)
AF:
0.00
AC:
0
AN:
60274
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152016
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74246
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41410
American (AMR)
AF:
0.00
AC:
0
AN:
15244
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10582
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67968
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
1
-
-
AGTPBP1-related disorder (1)
1
-
-
Neurodegeneration, childhood-onset, with cerebellar atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.78
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.42
Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs780631499; hg19: chr9-88203379; API