Genetic Variant PDX1:c.406+512G>T (chr13-27921056-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000209.4(PDX1):c.406+512G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,136 control chromosomes in the GnomAD database, including 4,006 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4006 hom., cov: 33)

Consequence

PDX1
NM_000209.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.510

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4 link	c.406+512G>T		intron_variant	Intron 1 of 1	ENST00000381033.5	NP_000200.1	P52945

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5 link	c.406+512G>T		intron_variant	Intron 1 of 1	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32758

AN:

152018

Hom.:

4007

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.330

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.444

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.241

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.215

AC:

32750

AN:

152136

Hom.:

4006

Cov.:

AF XY:

0.221

AC XY:

16409

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.126

AC:

5237

AN:

41514

American (AMR)

AF:

0.330

AC:

5052

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1081

AN:

3468

East Asian (EAS)

AF:

0.443

AC:

2283

AN:

5154

South Asian (SAS)

AF:

0.167

AC:

806

AN:

4820

European-Finnish (FIN)

AF:

0.251

AC:

2658

AN:

10576

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.219

AC:

14904

AN:

67994

Other (OTH)

AF:

0.240

AC:

506

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1258

2515

3773

5030

6288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.163

Hom.:

490

Bravo

AF:

0.221

Asia WGS

AF:

0.264

AC:

917

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

9.5

(source)

DANN

Benign

0.86

PhyloP100

0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

Other links and lift over