rs137852783
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000209.4(PDX1):c.226G>A(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00489 in 1,545,430 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0032 ( 3 hom., cov: 33)
Exomes 𝑓: 0.0051 ( 23 hom. )
Consequence
PDX1
NM_000209.4 missense
NM_000209.4 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 6.18
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.005629629).
BP6
Variant 13-27920364-G-A is Benign according to our data. Variant chr13-27920364-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8859.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Likely_benign=5, Likely_pathogenic=1}. Variant chr13-27920364-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00507 (7064/1393306) while in subpopulation NFE AF= 0.00593 (6382/1076684). AF 95% confidence interval is 0.00581. There are 23 homozygotes in gnomad4_exome. There are 3363 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDX1 | NM_000209.4 | c.226G>A | p.Asp76Asn | missense_variant | 1/2 | ENST00000381033.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDX1 | ENST00000381033.5 | c.226G>A | p.Asp76Asn | missense_variant | 1/2 | 1 | NM_000209.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00320 AC: 487AN: 152016Hom.: 3 Cov.: 33
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GnomAD3 exomes AF: 0.00288 AC: 416AN: 144486Hom.: 2 AF XY: 0.00308 AC XY: 240AN XY: 78048
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GnomAD4 exome AF: 0.00507 AC: 7064AN: 1393306Hom.: 23 Cov.: 33 AF XY: 0.00490 AC XY: 3363AN XY: 686990
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GnomAD4 genome AF: 0.00319 AC: 486AN: 152124Hom.: 3 Cov.: 33 AF XY: 0.00254 AC XY: 189AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 09, 2021 | The p.Asp76Asn variant in the PDX1 gene has been classified as benign because it has been identified in 0.49% (336/68440) of Northern European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 08, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2024 | Variant summary: PDX1 c.226G>A (p.Asp76Asn) results in a 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 0.0029 in 144486 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2303 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 benign. The following publications have been ascertained in the context of this evaluation (PMID: 10545531, 10720084, 10545530, 15170499). ClinVar contains an entry for this variant (Variation ID: 8859). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2021 | This variant is associated with the following publications: (PMID: 28323911, 15170499, 15277425, 19515026, 10720084, 24097065, 10545531, 10545530, 26669242) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 14, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 16, 2019 | - - |
Maturity onset diabetes mellitus in young Pathogenic:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2022 | This alteration is classified as likely 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. - |
Benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 10, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | research | Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar | Dec 18, 2017 | - - |
Diabetes mellitus type 2, susceptibility to Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Nov 01, 1999 | - - |
Type 2 diabetes mellitus Benign:1
Benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 10, 2023 | - - |
Monogenic diabetes Benign:1
Benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Oct 12, 2018 | ACMG criteria: BS2 (cases=controls in PMID 17592437, 21569088), BS1 (0.4% MAF in gnomAD)= benign; REVEL 0.245 +BP4/4 predictors + PP3/6 predictors: conflicting evidence, not using) OMIM suggests that it is a susceptability factor for T2DM - |
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.Asp76Asn variant in PDX1 (sometimes called IPF1) has been reported in at least 32 individuals with Maturity-Onset Diabetes of the Young (PMID: 15277425, 10545531, 10545530, 17592437), and has been identified in 0.4909% (336/68440) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852783). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. However, this variant does not segregate with disease in many families, including sibling pairs (PMID: 10545531, 15277425). This variant has also been reported as a benign variant, likely benign variant, VUS, likely pathogenic variant, and risk factor for diabetes in ClinVar (Variation ID: 8859). In vitro functional studies provide some evidence that the p.Asp76Asn variant may slightly impact protein function, but this evidence is not conclusive (PMID: 10545531). These types of assays may not accurately represent biological function. Computational prediction tools 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 Maturity-Onset Diabetes of the Young in an autosomal dominant manner based on a higher than expected frequency in control cohorts and nonsegregation with MODY. ACMG/AMP Criteria applied: BS2, BS4, BP4 (Richards 2015). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at