13-27920235-C-A

Position:

chr13-27920235-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 5.58

Variant links:

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]

PDX1 links:

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=0.03478363).

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: {Likely_benign=2, Uncertain_significance=4, Benign=3}. 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 GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDX1	NM_000209.4 linkuse as main transcript	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 linkuse as main transcript	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.:

Cov.:

show subpopulations

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.:

AF XY:

0.00289

AC XY:

222

AN XY:

76904

show subpopulations

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.:

Cov.:

AF XY:

0.00212

AC XY:

1462

AN XY:

688488

show subpopulations

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.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74464

show subpopulations

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.:

Bravo

AF:

0.00198

ExAC

AF:

0.00141

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 4

Uncertain:2

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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2024	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) -

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] -

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. -

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

MetaRNN

Benign

0.035

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

0.98

MPC

2.1

ClinPred

0.044

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over