rs137852783

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000209.4(PDX1):c.226G>A(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00489 in 1,545,430 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 23 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:13

Conservation

PhyloP100: 6.18

Publications

37 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: 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 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.005629629).

BP6

Variant 13-27920364-G-A is Benign according to our data. Variant chr13-27920364-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8859.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00319 (486/152124) while in subpopulation NFE AF = 0.00489 (332/67962). AF 95% confidence interval is 0.00445. There are 3 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4 link	c.226G>A	p.Asp76Asn	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.226G>A	p.Asp76Asn	missense_variant	Exon 1 of 2	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

AF:

0.00320

AC:

487

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00488

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00288

AC:

416

AN:

144486

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00244

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00263

GnomAD4 exome

AF:

0.00507

AC:

7064

AN:

1393306

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

3363

AN XY:

686990

show subpopulations

African (AFR)

AF:

0.000985

AC:

AN:

31458

American (AMR)

AF:

0.00309

AC:

110

AN:

35590

Ashkenazi Jewish (ASJ)

AF:

0.00239

AC:

AN:

25082

East Asian (EAS)

AF:

0.00

AC:

AN:

35672

South Asian (SAS)

AF:

0.00209

AC:

165

AN:

79024

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

47604

Middle Eastern (MID)

AF:

0.00222

AC:

AN:

4504

European-Non Finnish (NFE)

AF:

0.00593

AC:

6382

AN:

1076684

Other (OTH)

AF:

0.00473

AC:

273

AN:

57688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

388

775

1163

1550

1938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00319

AC:

486

AN:

152124

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41508

American (AMR)

AF:

0.00425

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00373

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00489

AC:

332

AN:

67962

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00362

Hom.:

Bravo

AF:

0.00399

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000291

AC:

ESP6500EA

AF:

0.00317

AC:

ExAC

AF:

0.00110

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 08, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp76Asn variant in the PDX1 gene has been classified as benign because it has been identified in 0.49% (336/68440) of Northern European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Apr 12, 2024

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: PDX1 c.226G>A (p.Asp76Asn) results in a 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 0.0029 in 144486 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2303 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. The following publications have been ascertained in the context of this evaluation (PMID: 10545531, 10720084, 10545530, 15170499). ClinVar contains an entry for this variant (Variation ID: 8859). Based on the evidence outlined above, the variant was classified as likely benign. -

Maturity onset diabetes mellitus in young

Pathogenic:1Benign:2

Jun 22, 2022

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. -

Dec 18, 2017

Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 10, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

May 20, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28323911, 15170499, 15277425, 19515026, 10720084, 24097065, 10545531, 10545530, 26669242) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diabetes mellitus type 2, susceptibility to

Uncertain:1

Nov 01, 1999

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Type 2 diabetes mellitus

Benign:1

Dec 10, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Oct 12, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BS2 (cases=controls in PMID 17592437, 21569088), BS1 (0.4% MAF in gnomAD)= benign; REVEL 0.245 +BP4/4 predictors + PP3/6 predictors: conflicting evidence, not using) OMIM suggests that it is a susceptability factor for T2DM -

Maturity-onset diabetes of the young type 4

Benign:1

Jan 22, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Asp76Asn variant in PDX1 (sometimes called IPF1) has been reported in at least 32 individuals with Maturity-Onset Diabetes of the Young (PMID: 15277425, 10545531, 10545530, 17592437), and has been identified in 0.4909% (336/68440) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852783). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. However, this variant does not segregate with disease in many families, including sibling pairs (PMID: 10545531, 15277425). This variant has also been reported as a benign variant, likely benign variant, VUS, likely pathogenic variant, and risk factor for diabetes in ClinVar (Variation ID: 8859). In vitro functional studies provide some evidence that the p.Asp76Asn variant may slightly impact protein function, but this evidence is not conclusive (PMID: 10545531). These types of assays may not accurately represent biological function. Computational prediction tools 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 Maturity-Onset Diabetes of the Young in an autosomal dominant manner based on a higher than expected frequency in control cohorts and nonsegregation with MODY. ACMG/AMP Criteria applied: BS2, BS4, BP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

0.12

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0056

MetaSVM

Uncertain

-0.039

MutationAssessor

Benign

1.8

PhyloP100

6.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.7

REVEL

Benign

0.24

Sift

Uncertain

0.0030

Sift4G

Benign

0.14

Polyphen

0.48

Vest4

0.43

MVP

0.87

MPC

1.1

ClinPred

0.019

GERP RS

4.1

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.15

gMVP

0.55

Mutation Taster

=98/2

disease causing (ClinVar)

(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