13-27920235-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2PP3BS1_Supporting

The NM_000209.4(PDX1):c.97C>T(p.Pro33Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000652 in 1,548,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.58

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young type 4
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pancreatic agenesis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
permanent neonatal diabetes mellitus
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
monogenic diabetes
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pancreatic agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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 pancreatic agenesis 1, monogenic diabetes, pancreatic agenesis, maturity-onset diabetes of the young, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young type 4.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000695 (97/1396048) while in subpopulation MID AF = 0.000543 (3/5520). AF 95% confidence interval is 0.000147. There are 0 homozygotes in GnomAdExome4. There are 51 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 2	ENST00000381033.5	NP_000200.1	P52945

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5 link	c.97C>T	p.Pro33Ser	missense_variant	Exon 1 of 2	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000563

AC:

AN:

142222

AF XY:

0.0000650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000820

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000984

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000695

AC:

AN:

1396048

Hom.:

Cov.:

AF XY:

0.0000741

AC XY:

AN XY:

688488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31440

American (AMR)

AF:

0.0000561

AC:

AN:

35628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25122

East Asian (EAS)

AF:

0.00

AC:

AN:

35676

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47714

Middle Eastern (MID)

AF:

0.000543

AC:

AN:

5520

European-Non Finnish (NFE)

AF:

0.0000761

AC:

AN:

1077984

Other (OTH)

AF:

0.000156

AC:

AN:

57854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67982

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000122

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000156

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PDX1 c.97C>T (p.Pro33Ser) 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 5.6e-05 in 142222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.97C>T has been reported in the literature in a study examining a large cohort of individuals from the UK Biobank, where it was found in both individuals with a diagnosis of diabetes and in individuals without a diabetes diagnosis (Billings_2022). However, it was not determined/specified whether these affected individuals had any indications suggesting a diagnosis of Monogenic Diabetes or Maturity Onset Diabetes Of The Young (MODY) more specifically, and those without a diagnosis were not clinically examined as part of the study to rule out the potential for cases going undiagnosed. Therefore, this report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 32041611). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4;C3891828:Pancreatic agenesis 1

Uncertain:1

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with PDX1-related conditions. This variant is present in population databases (rs192902098, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 33 of the PDX1 protein (p.Pro33Ser). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDX1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.9

PhyloP100

5.6

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.61

MutPred

0.49

Gain of catalytic residue at Y37 (P = 3e-04);

MVP

0.90

MPC

1.9

ClinPred

0.77

GERP RS

5.5

PromoterAI

-0.0015

Neutral

(source)

Varity_R

0.66

gMVP

0.69

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over