rs193929377

Variant names:

• chr13-27920320-GC-G
• rs193929377
• NM_000209.4:c.188delC

Your query was ambiguous. Multiple possible variants found:

• chr13-27920320-GC-G
• chr13-27920320-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PS3 PP5

The NM_000209.4(PDX1):​c.188delC​(p.Pro63ArgfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,541,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001167854: Published functional studies demonstrate that the variant results in increased binding of coactivator p300 compared to wild-type, suggesting a dominant negative effect due to depletion of available p300 for target gene activation (PMID:15001545)" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: PDX1 NM_000209.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 0.540
• Publications: 16 publications found

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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001167854: Published functional studies demonstrate that the variant results in increased binding of coactivator p300 compared to wild-type, suggesting a dominant negative effect due to depletion of available p300 for target gene activation (PMID: 15001545); SCV001423046: "In vitro functional studies provide some evidence that the p.Pro63Argfs variant may slightly impact protein function." PMID:15001545; SCV005685223: Functional studies show that this variant results in premature truncation of the PDX1 protein (Stoffers D et al., PMID: 9649577).; SCV002719153: "Protein analysis demonstrated 2 mutant PDX1 proteins produced by this variant: a smaller mutant protein which encodes a truncated amino-terminal protein lacking a DNA binding domain and a nuclear localization signal but including an unique carboxy-terminal sequence arising from the frame shift that is expected to be transcriptionally inactive and a larger mutant protein using an alternate, out-of-frame initiation codon that is returned to in-frame by the cytosine deletion and lacks the amino-terminal transactivation domain but includes the DNA-binding homeodomain and the carboxy-terminal domain, suggesting a dominant-negative mechanism (Stoffers DA et al. J. Clin. Invest., 1998 Jul;102:232-41)."
• PP5: Variant 13-27920320-GC-G is Pathogenic according to our data. Variant chr13-27920320-GC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21124.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000209.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDX1	NM_000209.4	MANE Select	c.188delC	p.Pro63ArgfsTer60	frameshift	Exon 1 of 2	NP_000200.1	P52945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDX1	ENST00000381033.5	TSL:1 MANE Select	c.188delC	p.Pro63ArgfsTer60	frameshift	Exon 1 of 2	ENSP00000370421.4	P52945

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000145 AC: 2 AN: 138298 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: 0.0000201

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.00000863 AC: 12 AN: 1389708 Hom.: 0 Cov.: 33 AF XY: 0.00000584 AC XY: 4 AN XY: 685020

African (AFR) AF: 0.00 AC: 0 AN: 31362

American (AMR) AF: 0.00 AC: 0 AN: 35432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24756

East Asian (EAS) AF: 0.00 AC: 0 AN: 35606

South Asian (SAS) AF: 0.00 AC: 0 AN: 78490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4784

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1074718

Other (OTH) AF: 0.0000174 AC: 1 AN: 57584

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Maturity-onset diabetes of the young type 4 (3)
2	1	-	not provided (3)
1	-	-	Maturity-onset diabetes of the young (1)
1	-	-	Maturity-onset diabetes of the young type 4;C3891828:Pancreatic agenesis 1 (1)
1	-	-	Pancreatic agenesis 1 (1)
1	-	-	Permanent neonatal diabetes mellitus (1)
1	-	-	Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4;C3891828:Pancreatic agenesis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=23/177	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193929377; hg19: chr13-28494457;