chr13-27920235-C-A

Variant names:

• chr13-27920235-C-A
• rs192902098
• NM_000209.4:c.97C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000209.4(PDX1):​c.97C>A​(p.Pro33Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,548,334 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (15 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 5.58

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.26592 (below the threshold of 3.09). Trascript score misZ: -1.1553 (below the threshold of 3.09). GenCC associations: The gene is linked to maturity-onset diabetes of the young type 4, pancreatic agenesis 1, monogenic diabetes, maturity-onset diabetes of the young, pancreatic agenesis, permanent neonatal diabetes mellitus.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03478363).
• BP6: Variant 13-27920235-C-A is Benign according to our data. Variant chr13-27920235-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36414.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, Benign=3}. Variant chr13-27920235-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0018 (274/152286) while in subpopulation AMR AF = 0.0049 (75/15308). AF 95% confidence interval is 0.00401. There are 2 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4	c.97C>A	p.Pro33Thr	missense_variant	Exon 1 of 2	ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5	c.97C>A	p.Pro33Thr	missense_variant	Exon 1 of 2	1	NM_000209.4	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00256 AC: 364 AN: 142222 AF XY: 0.00289

Gnomad AFR exome AF: 0.000300

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000857

Gnomad EAS exome AF: 0.000570

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00201 AC: 2808 AN: 1396048 Hom.: 15 Cov.: 33 AF XY: 0.00212 AC XY: 1462 AN XY: 688488

Gnomad4 AFR exome AF: 0.000477 AC: 15 AN: 31440

Gnomad4 AMR exome AF: 0.00264 AC: 94 AN: 35628

Gnomad4 ASJ exome AF: 0.000438 AC: 11 AN: 25122

Gnomad4 EAS exome AF: 0.000140 AC: 5 AN: 35676

Gnomad4 SAS exome AF: 0.00607 AC: 480 AN: 79110

Gnomad4 FIN exome AF: 0.00136 AC: 65 AN: 47714

Gnomad4 NFE exome AF: 0.00184 AC: 1982 AN: 1077984

Gnomad4 Remaining exome AF: 0.00228 AC: 132 AN: 57854

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74464

Gnomad4 AFR AF: 0.000481 AC: 0.000480815 AN: 0.000480815

Gnomad4 AMR AF: 0.00490 AC: 0.0048994 AN: 0.0048994

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000581 AC: 0.000581395 AN: 0.000581395

Gnomad4 SAS AF: 0.00455 AC: 0.00455298 AN: 0.00455298

Gnomad4 FIN AF: 0.000565 AC: 0.000564865 AN: 0.000564865

Gnomad4 NFE AF: 0.00206 AC: 0.00205937 AN: 0.00205937

Gnomad4 OTH AF: 0.00284 AC: 0.00284091 AN: 0.00284091

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00198

ExAC AF: 0.00141 AC: 90

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 4 Uncertain:2

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Pro33Thr variant in PDX1 has been reported in 1 individual with maturity-onset diabetes of the young type 4 (PMID: 16092045), but has been identified in 0.7% (164/22330) of South Asian chromosomes as well as other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs192902098). This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 36414). In vitro functional studies provide some evidence that the p.Pro33Thr variant may impact protein function (PMID: 16092045, 30930126). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro33Thr variant is uncertain. ACMG/AMP Criteria applied: BA1, PS3_moderate, PP3 (Richards 2015). -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Aug 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with MODY, type 2 diabetes, gestational diabetes, and ketosis-prone diabetes in published literature (PMID: 16092045, 21569088, 19228875), however, also reported in multiple unaffected family members and unaffected controls in these studies; Published functional studies demonstrate a damaging effect due to impaired DNA-binding activity of the protein and misregulation of transcriptional targets (PMID: 16092045, 30930126); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10720084, 12618559, 26543388, 21569088, 30709774, 19228875, 27879211, 29439679, 30930126, 27884173, 34426522, 33565752, Harris2021[CaseReport], 33795639, 34278679, 34741762, 36208030, 34938542, 34988346, 36100423, 35333605, 36178555, 36208343, 16092045) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jan 16, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant, PDX1 (legacy gene name IPF1) c.97C>A (p.Pro33Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 169614 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD). The observed variant frequency is approximately 1844 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. However, the phenotype of MODY4 and/or other forms of monogenic/polygenic diabetes in the control individuals within the gnomAD database cannot be excluded. The variant c.97C>A has been reported in the literature in individuals within a single family affected with MODY4 (Gragnoli_2005). However, this study predated the emergence of large control databases such as gnomAD and ExAC. In another report of its presence in an individual(s) with ketone-prone diabetes, the authors conclude that this phenotype is not predominantly a Monogenic Diabetic Syndrome. Lastly, it has been reported in individuals with type 2 diabetes where it was identified at a similar frequency in cases as well as normoglycemic controls (Haaland_2009, Edghill_2011). Therefore, these reports do not provide unequivocal conclusions about association of the variant with MODY4 and favor a benign outcome consistent with its high frequency in controls. At least one publication reports a moderate (30-50%) reduction in DNA binding and transcriptional activation functions of this variant in vitro (Gragnoli_2005) however, the implications of this finding to the mechanism and pathophysiology of MOD4 are not clear. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -

Jul 31, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus Uncertain:1

Jul 18, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple individuals with type 2 diabetes mellitus and/or maturity-onset diabetes of the young (MODY) [PMID: 16092045, 19228875, 21569088] -

Maturity onset diabetes mellitus in young Benign:1

Jan 13, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Monogenic diabetes Benign:1

Jan 18, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: PP3 (REVEL 0.928 + 10 predictors) + BA1 (0.7% in gnomAD SA, 0.2% in gnomAD Latino and ENF) + PS3 (PMID 16092045, in vitro studies of P33T showed a reduction in DNA-binding and transcriptional activation functions as compared to the wild-type IPF1 protein), BS2 (Five cases and six well-phenotyped controls in PMID: 21569088)= benign Variant found in seven healthy people at risk for T2DM based on fam hx or BMI or lab results in PMID: 27879211, of these people, at least one was glucose tolerant and thin. Variant found in MODY cohort in PMID: 29439679 but authors say unlikely to be cause given frequency of variant in general population -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.035	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		2.1
ClinPred		0.044	T
GERP RS		5.5
Varity_R		0.74
gMVP		0.70
Mutation Taster		=15/85	disease causing

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

LitVar

Other links and lift over

dbSNP: rs192902098; hg19: chr13-28494372; COSMIC: COSV66847219; COSMIC: COSV66847219;