rs193922358
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000209.4(PDX1):c.725C>T(p.Pro242Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,506,836 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000209.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDX1 | NM_000209.4 | c.725C>T | p.Pro242Leu | missense_variant | 2/2 | ENST00000381033.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDX1 | ENST00000381033.5 | c.725C>T | p.Pro242Leu | missense_variant | 2/2 | 1 | NM_000209.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00117 AC: 178AN: 152100Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00120 AC: 128AN: 106960Hom.: 1 AF XY: 0.00131 AC XY: 77AN XY: 58560
GnomAD4 exome AF: 0.00150 AC: 2027AN: 1354630Hom.: 2 Cov.: 31 AF XY: 0.00144 AC XY: 961AN XY: 666564
GnomAD4 genome ? AF: 0.00117 AC: 178AN: 152206Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82AN XY: 74412
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 05, 2019 | Variant summary: The variant, PDX1 (legacy gene name IPF1) c.725C>T (p.Pro242Leu) 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 0.0013 in 134384 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1760 fold of 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. Mohan et al (Mohan_2018) state that the variant was found in similar frequencies in MODY cases and in general population in South India and suggests that the variant most likely have little to no effect on risk of developing MODY. The variant c.725C>T has been reported in the literature in individuals affected with MODY (Ang_2016, Chambers_2016). However, these reports do not provide unequivocal conclusions about association of the variant with the disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LP by Labcorp (2011). Low reads. Could not find any publications. - |
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 20, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2019 | This variant is associated with the following publications: (PMID: 29439679) - |
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 no sufficient evidence is found to ascertain the role of this particular variant rs193922358, yet. - |
PDX1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 14, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Maturity-onset diabetes of the young type 4 Benign:1
Benign, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Pro242Leu variant in PDX1 has been reported in at least 1 Asian individual with maturity-onset diabetes of the young type 4 (PMID: 27420379), and has been identified in 0.2% (124/58140) of European (non-Finnish) chromosomes and multiple other populations at lower frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922358). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 36411). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for MODY type 4 in an autosomal dominant manner based on computational tool predictions and the frequency of this variant in multiple populations. ACMG/AMP Criteria applied: BP4, BA1 (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at