chr19-804601-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002819.5(PTBP1):​c.505G>C​(p.Ala169Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,611,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A169V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PTBP1
NM_002819.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Publications

0 publications found
Variant links:
Genes affected
PTBP1 (HGNC:9583): (polypyrimidine tract binding protein 1) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA-binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has four repeats of quasi-RNA recognition motif (RRM) domains that bind RNAs. This protein binds to the intronic polypyrimidine tracts that requires pre-mRNA splicing and acts via the protein degradation ubiquitin-proteasome pathway. It may also promote the binding of U2 snRNP to pre-mRNAs. This protein is localized in the nucleoplasm and it is also detected in the perinucleolar structure. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08152151).
BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTBP1NM_002819.5 linkc.505G>C p.Ala169Pro missense_variant Exon 6 of 15 ENST00000356948.11 NP_002810.1 P26599-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTBP1ENST00000356948.11 linkc.505G>C p.Ala169Pro missense_variant Exon 6 of 15 1 NM_002819.5 ENSP00000349428.4 P26599-3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152246
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000976
AC:
24
AN:
245938
AF XY:
0.0000373
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000698
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1459606
Hom.:
0
Cov.:
35
AF XY:
0.00000964
AC XY:
7
AN XY:
726134
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33464
American (AMR)
AF:
0.000515
AC:
23
AN:
44676
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26090
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86216
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51754
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111618
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60334
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152364
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74508
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41586
American (AMR)
AF:
0.000131
AC:
2
AN:
15312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
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:
0.0000264
ExAC
AF:
0.0000661
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 05, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.505G>C (p.A169P) alteration is located in exon 6 (coding exon 6) of the PTBP1 gene. This alteration results from a G to C substitution at nucleotide position 505, causing the alanine (A) at amino acid position 169 to be replaced by a proline (P). 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
0.23
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.12
.;.;T;.;.;T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
T;D;T;D;T;T;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.082
T;T;T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.4
M;.;M;.;M;.;.
PhyloP100
4.8
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.5
N;.;N;.;N;.;.
REVEL
Benign
0.17
Sift
Benign
0.24
T;.;T;.;T;.;.
Sift4G
Benign
0.13
T;T;T;T;T;T;T
Polyphen
0.021, 0.0080
.;.;B;.;B;.;.
Vest4
0.62
MutPred
0.49
Loss of stability (P = 0.0307);.;Loss of stability (P = 0.0307);.;Loss of stability (P = 0.0307);.;.;
MVP
0.59
MPC
1.4
ClinPred
0.11
T
GERP RS
4.8
PromoterAI
0.0033
Neutral
Varity_R
0.49
gMVP
0.57
Mutation Taster
=74/26
polymorphism

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

Other links and lift over

dbSNP: rs571820277; hg19: chr19-804601; API