10-23192538-C-T
Position:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_178161.3(PTF1A):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,588,374 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 (★★).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 0 hom. )
Consequence
PTF1A
NM_178161.3 missense
NM_178161.3 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 2.76
Genes affected
PTF1A (HGNC:23734): (pancreas associated transcription factor 1a) This gene encodes a protein that is a component of the pancreas transcription factor 1 complex (PTF1) and is known to have a role in mammalian pancreatic development. The protein plays a role in determining whether cells allocated to the pancreatic buds continue towards pancreatic organogenesis or revert back to duodenal fates. The protein is thought to be involved in the maintenance of exocrine pancreas-specific gene expression including elastase 1 and amylase. Mutations in this gene cause cerebellar agenesis and loss of expression is seen in ductal type pancreas cancers. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.098780155).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000283 (43/151988) while in subpopulation AMR AF= 0.000589 (9/15268). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTF1A | ENST00000376504.4 | c.8C>T | p.Ala3Val | missense_variant | 1/2 | 1 | NM_178161.3 | ENSP00000365687.3 | ||
PTF1A | ENST00000638469.1 | c.-26C>T | upstream_gene_variant | 5 | ENSP00000491649.1 |
Frequencies
GnomAD3 genomes AF: 0.000283 AC: 43AN: 151988Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
43
AN:
151988
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000203 AC: 45AN: 221408Hom.: 0 AF XY: 0.000148 AC XY: 18AN XY: 121664
GnomAD3 exomes
AF:
AC:
45
AN:
221408
Hom.:
AF XY:
AC XY:
18
AN XY:
121664
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000374 AC: 537AN: 1436386Hom.: 0 Cov.: 33 AF XY: 0.000329 AC XY: 235AN XY: 714814
GnomAD4 exome
AF:
AC:
537
AN:
1436386
Hom.:
Cov.:
33
AF XY:
AC XY:
235
AN XY:
714814
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000283 AC: 43AN: 151988Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74230
GnomAD4 genome
AF:
AC:
43
AN:
151988
Hom.:
Cov.:
32
AF XY:
AC XY:
21
AN XY:
74230
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
3
ExAC
AF:
AC:
22
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome;C4014737:Pancreatic agenesis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 11, 2022 | - - |
Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 15, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3 of the PTF1A protein (p.Ala3Val). This variant is present in population databases (rs146089816, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PTF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 880486). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at