rs193922358

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000209.4(PDX1):​c.725C>A​(p.Pro242Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,354,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P242L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

PDX1
NM_000209.4 missense

Scores

1
2
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.339
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]

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. 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 maturity-onset diabetes of the young type 4, pancreatic agenesis 1, monogenic diabetes, maturity-onset diabetes of the young, pancreatic agenesis, permanent neonatal diabetes mellitus.
BP4
Computational evidence support a benign effect (MetaRNN=0.2579918).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PDX1NM_000209.4 linkc.725C>A p.Pro242Gln 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
PDX1ENST00000381033.5 linkc.725C>A p.Pro242Gln missense_variant Exon 2 of 2 1 NM_000209.4 ENSP00000370421.4 P52945

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000295
AC:
4
AN:
1354630
Hom.:
0
Cov.:
31
AF XY:
0.00000150
AC XY:
1
AN XY:
666564
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
28642
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
31732
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
22360
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
33910
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
72292
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
40814
Gnomad4 NFE exome
AF:
0.00000376
AC:
4
AN:
1064736
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
56244
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
16
DANN
Benign
0.96
DEOGEN2
Uncertain
0.46
T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.47
T
M_CAP
Pathogenic
0.83
D
MetaRNN
Benign
0.26
T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
0.83
N
REVEL
Benign
0.13
Sift
Benign
0.17
T
Sift4G
Benign
0.64
T
Polyphen
0.0010
B
Vest4
0.29
MutPred
0.39
Gain of catalytic residue at P243 (P = 5e-04);
MVP
0.54
MPC
0.91
ClinPred
0.077
T
GERP RS
1.6
Varity_R
0.032
gMVP
0.51
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs193922358; hg19: chr13-28498711; API