rs192902098

chr13-27920235-C-Achr13-27920235-C-Gchr13-27920235-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. 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

Verdict is Benign. Variant got -13 ACMG points.

• 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: {Benign=3, Uncertain_significance=4, Likely_benign=2}. Variant chr13-27920235-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00201 (2808/1396048) while in subpopulation SAS AF= 0.00607 (480/79110). AF 95% confidence interval is 0.00562. There are 15 homozygotes in gnomad4_exome. There are 1462 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDX1	NM_000209.4	c.97C>A	p.Pro33Thr	missense_variant	1/2	ENST00000381033.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDX1	ENST00000381033.5	c.97C>A	p.Pro33Thr	missense_variant	1/2	1	NM_000209.4	P1

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

GnomAD3 exomes AF: 0.00256 AC: 364 AN: 142222 Hom.: 2 AF XY: 0.00289 AC XY: 222 AN XY: 76904

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 SAS exome AF: 0.00734

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

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000438

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.00607

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00228

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

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00112 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

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2022	Identified in patients with MODY, type 2 diabetes, gestational diabetes, and ketosis-prone diabetes in published literature (Gragnoli et al., 2005; Edghill et al., 2011; Haaland et al., 2009), 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 (Gragnoli et al., 2005; Wang et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10720084, 12618559, 26543388, 21569088, 30709774, 16092045, 19228875, 27879211, 29439679, 30930126, 27884173, 34426522, 33565752, Harris2021[CaseReport], 33795639, 34278679, 34741762, 34938542, 34988346, 36100423) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2019	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. -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 18, 2019

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] -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 18, 2019

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 -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2020

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. -

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
MutationTaster	Benign	1.0	D
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

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;