rs193922358

chr13-27924574-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 0.339

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02783981).
• BP6: Variant 13-27924574-C-T is Benign according to our data. Variant chr13-27924574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36411.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=3}. Variant chr13-27924574-C-T is described in Lovd as [Likely_benign].

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: 178 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00120 AC: 128 AN: 106960 Hom.: 1 AF XY: 0.00131 AC XY: 77 AN XY: 58560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00149

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.00150 AC: 2027 AN: 1354630 Hom.: 2 Cov.: 31 AF XY: 0.00144 AC XY: 961 AN XY: 666564

Gnomad4 AFR exome AF: 0.0000698

Gnomad4 AMR exome AF: 0.000189

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000295

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.000490

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.000996

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74412

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.000986

ESP6500AA AF: 0.000413 AC: 1

ESP6500EA AF: 0.000738 AC: 4

ExAC AF: 0.000914 AC: 83

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2019	- -

not provided Uncertain:1 Benign:2

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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 20, 2022	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.51	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.35
MVP		0.53
MPC		1.4
ClinPred		0.021	T
GERP RS		1.6
Varity_R		0.035
gMVP		0.49

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: rs193922358; hg19: chr13-28498711; COSMIC: COSV66847487;