rs9581943

Variant names:

• chr13-27919860-G-A
• rs9581943
• NM_000209.4:c.-279G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000209.4(PDX1):​c.-279G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 152,138 control chromosomes in the GnomAD database, including 8,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.32 (8883 hom., cov: 33)
• Consequence: PDX1 NM_000209.4 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.20
• Publications: 39 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, 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 13-27919860-G-A is Benign according to our data. Variant chr13-27919860-G-A is described in ClinVar as Benign. ClinVar VariationId is 669733.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4	c.-279G>A		upstream_gene_variant		ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5	c.-279G>A		upstream_gene_variant		1	NM_000209.4	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48137 AN: 152020 Hom.: 8881 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.317 AC: 48155 AN: 152138 Hom.: 8883 Cov.: 33 AF XY: 0.320 AC XY: 23775 AN XY: 74368

African (AFR) AF: 0.122 AC: 5084 AN: 41536

American (AMR) AF: 0.279 AC: 4271 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1174 AN: 3468

East Asian (EAS) AF: 0.379 AC: 1952 AN: 5150

South Asian (SAS) AF: 0.525 AC: 2529 AN: 4818

European-Finnish (FIN) AF: 0.390 AC: 4121 AN: 10576

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27804 AN: 67972

Other (OTH) AF: 0.330 AC: 698 AN: 2116

Alfa AF: 0.378 Hom.: 28767

Bravo AF: 0.293

Asia WGS AF: 0.428 AC: 1487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.73
PhyloP100		3.2
PromoterAI		0.24	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9581943; hg19: chr13-28493997;