13-27924565-C-A

Variant names:

• chr13-27924565-C-A
• rs199644078
• NM_000209.4:c.716C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000209.4(PDX1):​c.716C>A​(p.Pro239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,502,110 control chromosomes in the GnomAD database, including 46 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P239L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (28 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.961
• Publications: 12 publications found

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

ACMG classification

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=0.0057828426).
• BP6: Variant 13-27924565-C-A is Benign according to our data. Variant chr13-27924565-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129881.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0094 (1431/152158) while in subpopulation AFR AF = 0.0235 (975/41532). AF 95% confidence interval is 0.0223. There are 18 homozygotes in GnomAd4. There are 682 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4	c.716C>A	p.Pro239Gln	missense_variant	Exon 2 of 2	ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5	c.716C>A	p.Pro239Gln	missense_variant	Exon 2 of 2	1	NM_000209.4	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1417 AN: 152050 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00597 AC: 651 AN: 109026 AF XY: 0.00599

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00555

Gnomad EAS exome AF: 0.00126

Gnomad FIN exome AF: 0.00998

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00443 AC: 5977 AN: 1349952 Hom.: 28 Cov.: 31 AF XY: 0.00448 AC XY: 2973 AN XY: 664292

African (AFR) AF: 0.0252 AC: 714 AN: 28290

American (AMR) AF: 0.00322 AC: 99 AN: 30736

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 72 AN: 22338

East Asian (EAS) AF: 0.000566 AC: 19 AN: 33570

South Asian (SAS) AF: 0.00604 AC: 434 AN: 71804

European-Finnish (FIN) AF: 0.00776 AC: 321 AN: 41354

Middle Eastern (MID) AF: 0.00284 AC: 11 AN: 3868

European-Non Finnish (NFE) AF: 0.00378 AC: 4014 AN: 1062078

Other (OTH) AF: 0.00524 AC: 293 AN: 55914

GnomAD4 genome AF: 0.00940 AC: 1431 AN: 152158 Hom.: 18 Cov.: 32 AF XY: 0.00917 AC XY: 682 AN XY: 74396

African (AFR) AF: 0.0235 AC: 975 AN: 41532

American (AMR) AF: 0.00575 AC: 88 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5154

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.00416 AC: 44 AN: 10586

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00365 AC: 248 AN: 67976

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00678 Hom.: 2

Bravo AF: 0.0103

ESP6500AA AF: 0.0127 AC: 48

ESP6500EA AF: 0.00202 AC: 15

ExAC AF: 0.00438 AC: 423

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11270685, 27884173, 24097065) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDX1: BS1, BS2 -

Feb 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Mar 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2023

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.716C>A (p.Pro239Gln) 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 0.006 in 109586 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency significantly exceeds 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. c.716C>A has been reported in the literature in individuals affected with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (example, Weng_2001, Weng_2002, Lindgren_2002, Haaland_2009, Huang_2002, Zhang_2004). In our ascertainment of families with this variant, 10 transmissions of the variant allele and 6 transmissions of the reference allele to affected individuals was reported supporting lack of segregation with a disease phenotype. In our ascertainment, the penetrance of Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (0.53) due to this variant appears to be lower than expected (0.8), therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function (example, Weng_2001). The most pronounced variant effect results in normal expression and binding activity to the insulin gene promoter but reduced activation of the insulin-gene transcription in response to increased glucose concentrations compared with the wild-type IPF1 protein. The following publications have been ascertained in the context of this evaluation (PMID: 11270685, 11772903, 11978663, 15111508, 19228875, 12099699, 15028942, 12677187). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Dec 27, 2023

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.Pro239Gln variant in PDX1 is classified as benign because it has been identified in 2.8% (351/12426) of African/African-American chromosomes, including 9 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Pancreatic hypoplasia Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Potent homozygous mutations in the PDX1 gene can lead to pancreatic agenesis/pancreatic hypoplasia and neonatal diabetes mellitus. However, the role of this particular variant (rs199644078) of PDX1 in pancreatic agenesis/hypoplasia and neonatal diabetes mellitus remains uncertain. -

Maturity onset diabetes mellitus in young Benign:1

May 05, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Aug 14, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BA1 (2.8% in gnomAD African)= benign (REVEL score 0.221 + PP3 (3 predictors) + BP4 (8 predictors)= conflicting evidence, not using) -

Maturity-onset diabetes of the young type 4 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.96
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.22
Sift	Uncertain	0.015	D
Sift4G	Benign	0.19	T
Polyphen		0.024	B
Vest4		0.24
MVP		0.60
MPC		1.0
ClinPred		0.0094	T
GERP RS		2.8
Varity_R		0.079
gMVP		0.58
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199644078; hg19: chr13-28498702;