13-27920235-C-G

Position:

• chr13-27920235-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 5.58

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 Likely_benign. Variant got -3 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: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDX1	NM_000209.4	c.97C>G	p.Pro33Ala	missense_variant	1/2	ENST00000381033.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDX1	ENST00000381033.5	c.97C>G	p.Pro33Ala	missense_variant	1/2	1	NM_000209.4	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152176 Hom.: 0 Cov.: 33

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: 49 AN: 142222 Hom.: 0 AF XY: 0.000351 AC XY: 27 AN XY: 76904

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.: 1 Cov.: 33 AF XY: 0.000153 AC XY: 105 AN XY: 688486

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: 27 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74464

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.: 0

Bravo AF: 0.000276

ExAC AF: 0.0000938 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2021	This variant has been observed in individual(s) with clinical features of early onset diabetes (PMID: 34135026). While this variant is present in population databases (rs192902098), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces proline with alanine at codon 33 of the PDX1 protein (p.Pro33Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDX1 protein function. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.047	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.45		Gain of catalytic residue at F28 (P = 0.002);
MVP		0.88
MPC		1.8
ClinPred		0.12	T
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

Other links and lift over

dbSNP: rs192902098; hg19: chr13-28494372;