rs199644078

chr13-27924565-C-Achr13-27924565-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. 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. 13/20 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 0.0094 (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

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 Benign. Variant got -13 ACMG points.

• 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 id is 129881.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=8, Uncertain_significance=1}. Variant chr13-27924565-C-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDX1	NM_000209.4	c.716C>A	p.Pro239Gln	missense_variant	2/2	ENST00000381033.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDX1	ENST00000381033.5	c.716C>A	p.Pro239Gln	missense_variant	2/2	1	NM_000209.4	P1

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

GnomAD3 exomes AF: 0.00597 AC: 651 AN: 109026 Hom.: 6 AF XY: 0.00599 AC XY: 362 AN XY: 60462

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 SAS exome AF: 0.00734

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

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.000566

Gnomad4 SAS exome AF: 0.00604

Gnomad4 FIN exome AF: 0.00776

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00524

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

Gnomad4 AFR AF: 0.0235

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00416

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00705 Hom.: 1

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 11270685, 27884173, 24097065) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PDX1: BS1, BS2 -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 09, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2023	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. -

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, the role of this particular variant (rs199644078) of PDX1 in pancreatic agenesis/hypoplasia and neonatal diabetes mellitus remains uncertain. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Aug 14, 2018

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 mellitus in young Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2016

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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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
MutationTaster	Benign	0.99	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs199644078; hg19: chr13-28498702;