NM_000209.4:c.820G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_000209.4(PDX1):c.820G>A(p.Val274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000303 in 1,319,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V274F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.179

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young type 4
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pancreatic agenesis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
permanent neonatal diabetes mellitus
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
monogenic diabetes
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pancreatic agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.26592 (below the threshold of 3.09). Trascript score misZ: -1.1553 (below the threshold of 3.09). GenCC associations: The gene is linked to pancreatic agenesis 1, monogenic diabetes, pancreatic agenesis, maturity-onset diabetes of the young, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young type 4.

BP4

Computational evidence support a benign effect (MetaRNN=0.05113843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4 link	c.820G>A	p.Val274Ile	missense_variant	Exon 2 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.820G>A	p.Val274Ile	missense_variant	Exon 2 of 2	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

83252

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000303

AC:

AN:

1319012

Hom.:

Cov.:

AF XY:

0.00000308

AC XY:

AN XY:

649234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27050

American (AMR)

AF:

0.0000364

AC:

AN:

27476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23504

East Asian (EAS)

AF:

0.00

AC:

AN:

29502

South Asian (SAS)

AF:

0.00

AC:

AN:

70882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3930

European-Non Finnish (NFE)

AF:

0.00000286

AC:

AN:

1048916

Other (OTH)

AF:

0.00

AC:

AN:

54858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 274 of the PDX1 protein (p.Val274Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDX1-related conditions. 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 with a negative predictive value of 95%. 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

Benign

0.10

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.6

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.29

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.36

M_CAP

Benign

0.071

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

PhyloP100

0.18

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.15

REVEL

Benign

0.16

Sift

Benign

0.53

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.071

MutPred

0.30

Gain of catalytic residue at P276 (P = 0.0047);

MVP

0.49

MPC

0.78

ClinPred

0.035

GERP RS

1.5

Varity_R

0.021

gMVP

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over