rs137852787

Positions:

chr13-27924519-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000381033.5(PDX1):c.670G>A(p.Glu224Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000508 in 1,607,848 control chromosomes in the GnomAD database, including 7 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 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 7 hom. )

Consequence

PDX1
ENST00000381033.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6

Conservation

PhyloP100: 6.23

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008775234).

BP6

Variant 13-27924519-G-A is Benign according to our data. Variant chr13-27924519-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8863.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=5, Likely_benign=2}. Variant chr13-27924519-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000315 (48/152284) while in subpopulation SAS AF= 0.00972 (47/4834). AF 95% confidence interval is 0.00751. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDX1	NM_000209.4 linkuse as main transcript	c.670G>A	p.Glu224Lys	missense_variant	2/2	ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5 linkuse as main transcript	c.670G>A	p.Glu224Lys	missense_variant	2/2	1	NM_000209.4	ENSP00000370421	P1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152172

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:

0.00992

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00129

AC:

304

AN:

236358

Hom.:

AF XY:

0.00175

AC XY:

226

AN XY:

129080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00996

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000688

GnomAD4 exome

AF:

0.000528

AC:

769

AN:

1455564

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

544

AN XY:

723848

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00851

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000600

GnomAD4 genome

AF:

0.000315

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00972

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00151

AC:

182

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 11, 2022	DNA sequence analysis of the PDX1 gene demonstrated a sequence change, c.670G>A, in exon 2 that results in an amino acid change, p.Glu224Lys. This sequence change has been previously identified in the heterozygous state in individuals with diabetes (PMID: 14764823, 28095440). In vitro functional studies have indicated that this variant may reduce transactivation potential of IPF-1 (PMID: 17126328). This sequence change has been described in the gnomAD database with a frequency of 0.996% in the South Asian subpopulation (dbSNP rs137852787). The p.Glu224Lys change affects a highly conserved amino acid residue located in a domain of the PDX1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu224Lys substitution. Due to the high population frequency, insufficient evidences, and the lack of functional studies, the clinical significance of the p.Glu224Lys change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2022	Variant summary: PDX1 c.670G>A (p.Glu224Lys) results in a conservative amino acid change in the encoded protein sequence. Three 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 236358 control chromosomes, predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8000-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 South Asian origin. Nevertheless, c.670G>A has been reported in the literature in multiple individuals of Indian origin affected with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus (Cockburn_2004, Chapla_2015, Doddabelavangala_2017). However, these reports do not provide unequivocal conclusions about association of the variant with disease due to limited genotyping analysis or due to limited/inconclusive segregation data. One study carried out a comprehensive genomic analysis of 289 individuals from India, and concluded the variant to occur at a similar frequency in MODY cases and in the general population (Mohan_2018). Experimental evidence evaluating an impact on protein function demonstrated the variant affects PDX1 transactivation (Cockburn_2004, Liu_2006). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Type 2 diabetes mellitus

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Glu224Lys variant in PDX1 has been identified in at least 2 individuals with type 2 diabetes mellitus (PMID: 14764823), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Glu224Lys variant may slightly impact protein function (PMID: 14764823). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed missense c.670G>A(p.Glu224Lys) variant in PDX1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.1% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Benign/ Likely Benign/ Uncertain Significance. This variant is found as benign polymorphism primarily in populations of South Asian origin. However, these reports do not provide unequivocal conclusions about association of the variant with disease due to limited genotyping analysis or due to limited/inconclusive segregation data (Doddabelavangala Mruthyunjaya M, et. al., 2017;Chapla A, et. al., 2015). Computational evidence (Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster -Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid in PDX1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 224 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Published functional studies demonstrate a reduction in PDX1 transactivation, suggesting normal glucose homeostasis may be affected (Liu et al., 2006; Cockburn et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28095440, 16092045, 28862987, 27535533, 25581748, 28436541, 18360684, 31127050, 17126328, 25041077, 14764823, 22581228, 31366392, 29439679, 29473506, 34426522, 34741762, 32763092) -

Maturity-onset diabetes of the young type 4

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -

Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Dec 20, 2021

- -

Maturity onset diabetes mellitus in young

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2018

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. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 19, 2016

ACMG Criteria: PS3 (PMID:17126328,14764823), PP3, BS1 (1000G SAS), BS2 (type2diabetesgenetics.org), BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.031

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.61

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.049

Polyphen

0.69

Vest4

0.24

MutPred

0.65

Gain of catalytic residue at V220 (P = 0.001);

MVP

0.97

MPC

1.3

ClinPred

0.12

GERP RS

4.0

Varity_R

0.48

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over