13-27920239-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000209.4(PDX1):c.101C>T(p.Ala34Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,547,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A34A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.28

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDX1	NM_000209.4 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	1/2	ENST00000381033.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDX1	ENST00000381033.5 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant	1/2	1	NM_000209.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000848

AC:

AN:

141506

Hom.:

AF XY:

0.0000392

AC XY:

AN XY:

76622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000451

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1395608

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

688230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000393

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000326

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 01, 2021

This sequence change does not appear to have been previously described in individuals with PDX1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.045% in the Latino/Admixed American subpopulation (dbSNP rs750219172). The p.Ala34Val change affects a moderately 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.Ala34Val substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ala34Val change remains unknown at this time. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the PDX1 protein (p.Ala34Val). This variant is present in population databases (rs750219172, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PDX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1336622). 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 not expected to disrupt PDX1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.070

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.55

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.57

MutPred

0.39

Gain of catalytic residue at A34 (P = 0);

MVP

0.75

MPC

2.0

ClinPred

0.46

GERP RS

5.5

Varity_R

0.47

gMVP

0.60

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