rs199644078
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000209.4(PDX1):c.716C>A(p.Pro239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,502,110 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0094 ( 18 hom., cov: 32)
Exomes 𝑓: 0.0044 ( 28 hom. )
Consequence
PDX1
NM_000209.4 missense
NM_000209.4 missense
Scores
4
14
Clinical Significance
Conservation
PhyloP100: 0.961
Genes affected
PDX1 (HGNC:6107): (pancreatic and duodenal homeobox 1) The protein encoded by this gene is a transcriptional activator of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide, and glucose transporter type 2. The encoded nuclear protein is involved in the early development of the pancreas and plays a major role in glucose-dependent regulation of insulin gene expression. Defects in this gene are a cause of pancreatic agenesis, which can lead to early-onset insulin-dependent diabetes mellitus (IDDM), as well as maturity onset diabetes of the young type 4 (MODY4). [provided by RefSeq, Aug 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0057828426).
BP6
Variant 13-27924565-C-A is Benign according to our data. Variant chr13-27924565-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129881.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=8}. Variant chr13-27924565-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0094 (1431/152158) while in subpopulation AFR AF= 0.0235 (975/41532). AF 95% confidence interval is 0.0223. There are 18 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 18 AR gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00932 AC: 1417AN: 152050Hom.: 18 Cov.: 32
GnomAD3 genomes
AF:
AC:
1417
AN:
152050
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: 0.00597 AC: 651AN: 109026Hom.: 6 AF XY: 0.00599 AC XY: 362AN XY: 60462
GnomAD3 exomes
AF:
AC:
651
AN:
109026
Hom.:
AF XY:
AC XY:
362
AN XY:
60462
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: 0.00443 AC: 5977AN: 1349952Hom.: 28 Cov.: 31 AF XY: 0.00448 AC XY: 2973AN XY: 664292
GnomAD4 exome
AF:
AC:
5977
AN:
1349952
Hom.:
Cov.:
31
AF XY:
AC XY:
2973
AN XY:
664292
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 0.00940 AC: 1431AN: 152158Hom.: 18 Cov.: 32 AF XY: 0.00917 AC XY: 682AN XY: 74396
GnomAD4 genome
AF:
AC:
1431
AN:
152158
Hom.:
Cov.:
32
AF XY:
AC XY:
682
AN XY:
74396
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:
48
ESP6500EA
AF:
AC:
15
ExAC
AF:
AC:
423
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2019 | This variant is associated with the following publications: (PMID: 11270685, 27884173, 24097065) - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 27, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 14, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | PDX1: BS1, BS2 - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
not specified Benign:4
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 27, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 29, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 09, 2021 | The p.Pro239Gln variant in PDX1 is classified as benign because it has been identified in 2.8% (351/12426) of African/African-American chromosomes, including 9 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2023 | Variant summary: PDX1 c.716C>A (p.Pro239Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.006 in 109586 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency significantly exceeds the estimated maximal expected allele frequency for a pathogenic variant in PDX1 causing Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus phenotype (1.3e-06), strongly suggesting that the variant is benign. c.716C>A has been reported in the literature in individuals affected with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (example, Weng_2001, Weng_2002, Lindgren_2002, Haaland_2009, Huang_2002, Zhang_2004). In our ascertainment of families with this variant, 10 transmissions of the variant allele and 6 transmissions of the reference allele to affected individuals was reported supporting lack of segregation with a disease phenotype. In our ascertainment, the penetrance of Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (0.53) due to this variant appears to be lower than expected (0.8), therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function (example, Weng_2001). The most pronounced variant effect results in normal expression and binding activity to the insulin gene promoter but reduced activation of the insulin-gene transcription in response to increased glucose concentrations compared with the wild-type IPF1 protein. The following publications have been ascertained in the context of this evaluation (PMID: 11270685, 11772903, 11978663, 15111508, 19228875, 12099699, 15028942, 12677187). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Pancreatic hypoplasia Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However, the role of this particular variant (rs199644078) of PDX1 in pancreatic agenesis/hypoplasia and neonatal diabetes mellitus remains uncertain. - |
Monogenic diabetes Benign:1
| Benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Aug 14, 2018 | ACMG criteria: BA1 (2.8% in gnomAD African)= benign (REVEL score 0.221 + PP3 (3 predictors) + BP4 (8 predictors)= conflicting evidence, not using) - |
Maturity onset diabetes mellitus in young Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 05, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Maturity-onset diabetes of the young type 4 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
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