13-27920235-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000209.4(PDX1):c.97C>G(p.Pro33Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000163 in 1,548,332 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. P33T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 5.58

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047326803).

BP6

Variant 13-27920235-C-G is Benign according to our data. Variant chr13-27920235-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1256412.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000177 (27/152286) while in subpopulation EAS AF= 0.00407 (21/5160). AF 95% confidence interval is 0.00273. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4 link	c.97C>G	p.Pro33Ala	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>G	p.Pro33Ala	missense_variant	Exon 1 of 2	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00406

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000345

AC:

AN:

142222

Hom.:

AF XY:

0.000351

AC XY:

AN XY:

76904

show subpopulations

Gnomad AFR exome

AF:

0.000150

Gnomad AMR exome

AF:

0.0000410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00380

Gnomad SAS exome

AF:

0.0000896

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000787

Gnomad OTH exome

AF:

0.000239

GnomAD4 exome

AF:

0.000162

AC:

226

AN:

1396046

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

105

AN XY:

688486

show subpopulations

Gnomad4 AFR exome

AF:

0.0000954

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00345

Gnomad4 SAS exome

AF:

0.000101

Gnomad4 FIN exome

AF:

0.0000210

Gnomad4 NFE exome

AF:

0.0000742

Gnomad4 OTH exome

AF:

0.000138

GnomAD4 genome

AF:

0.000177

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00407

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000577

Hom.:

Bravo

AF:

0.000276

ExAC

AF:

0.0000938

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2022	Reported in a patient with suspected MODY from the published literature (Lee et al., 2021); Reported as part of a large study of dyslipidemia and metabolic disorders, but patient specific information was not provided (Dron et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34135026, 32041611) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2023	Variant summary: PDX1 c.97C>G (p.Pro33Ala) 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 0.00034 in 142222 control chromosomes. The observed variant frequency is approximately 275-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. c.97C>G has been reported in the literature in individuals affected with early onset diabetes, without strong evidence for causality (examples, Billings_2022, Dron_2020, Lee_2021, Johansson_2017, Ang_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Monogenic Diabetes (Maturity Onset Diabetes Of The Young 4)/Neonatal Diabetes Mellitus. 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: 27420379, 36208030, 32041611, 27913849, 34135026). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Oct 19, 2021

The heterozygous c.97C>G p.(Pro33Ala) variant identified in the PDX1 gene has previously been reported in the literature as variant of unknown significance in an individual with MODY IV [PMID:32041611]. The c.97C>G variant is observed in 31 control alleles (no homozygotes) with ~0.020-0.035% total allele frequency (predominantly in individuals of East Asian ancestry with ~0.25-0.4% subpopulation allele frequency) in gnomAD v2.1.1 and v3.1.1 databases, suggesting it is not a common benign variant in the populations represented in those databases. The predicted p.(Pro33Ala) variant resides in the 'transactivation domain', where other missense variants, including a different missense variant affecting the same residue (p.(Pro33Ser)), have been reported in the literature in individuals with MODY type IV and type 2 diabetes mellitus [PMIDs:10545530, 10545531, 24097065, 32041611, 33046911]. In silico prediction scores are in favor of damaging effect of this variant (CADD: 24.8, REVEL:0.718) to the function of the canonical transcript, however, there are no functional characterization studies performed. Based on available evidence, this heterozygous c.97C>G variant identified in the PDX1 gene is reported as Variant of Uncertain Significance. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.047

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.54

MutPred

0.45

Gain of catalytic residue at F28 (P = 0.002);

MVP

0.88

MPC

1.8

ClinPred

0.12

GERP RS

5.5

Varity_R

0.59

gMVP

0.62

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