rs530567443

Positions:

• chr13-27920303-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000209.4(PDX1):​c.165C>A​(p.Gly55Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000885 in 1,537,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: PDX1 NM_000209.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.444

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 13-27920303-C-A is Benign according to our data. Variant chr13-27920303-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 517723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-27920303-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.444 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDX1	NM_000209.4	c.165C>A	p.Gly55Gly	synonymous_variant	1/2	ENST00000381033.5	NP_000200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033.5	c.165C>A	p.Gly55Gly	synonymous_variant	1/2	1	NM_000209.4	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000718 AC: 94 AN: 130984 Hom.: 0 AF XY: 0.000729 AC XY: 52 AN XY: 71330

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.0000434

Gnomad ASJ exome AF: 0.000689

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00229

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000787

GnomAD4 exome AF: 0.000898 AC: 1244 AN: 1384996 Hom.: 0 Cov.: 33 AF XY: 0.000903 AC XY: 616 AN XY: 682544

Gnomad4 AFR exome AF: 0.0000328

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.000739

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.000987

Gnomad4 OTH exome AF: 0.000768

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74450

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00142 Hom.: 1

Bravo AF: 0.000453

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 16, 2020	- -

PDX1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.1
DANN	Benign	0.91

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

LitVar

Other links and lift over

dbSNP: rs530567443; hg19: chr13-28494440;