rs137852783

chr13-27920364-G-Achr13-27920364-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000209.4(PDX1):c.226G>A(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00489 in 1,545,430 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (23 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:12 O:1
• Conservation: PhyloP100: 6.18

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005629629).
• BP6: Variant 13-27920364-G-A is Benign according to our data. Variant chr13-27920364-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8859.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=8, Likely_benign=4, Likely_pathogenic=1}. Variant chr13-27920364-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00507 (7064/1393306) while in subpopulation NFE AF= 0.00593 (6382/1076684). AF 95% confidence interval is 0.00581. There are 23 homozygotes in gnomad4_exome. There are 3363 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDX1	NM_000209.4	c.226G>A	p.Asp76Asn	missense_variant	1/2	ENST00000381033.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDX1	ENST00000381033.5	c.226G>A	p.Asp76Asn	missense_variant	1/2	1	NM_000209.4	P1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152016 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00288 AC: 416 AN: 144486 Hom.: 2 AF XY: 0.00308 AC XY: 240 AN XY: 78048

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00244

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00182

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00507 AC: 7064 AN: 1393306 Hom.: 23 Cov.: 33 AF XY: 0.00490 AC XY: 3363 AN XY: 686990

Gnomad4 AFR exome AF: 0.000985

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00239

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00593

Gnomad4 OTH exome AF: 0.00473

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152124 Hom.: 3 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74364

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00489

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00331 Hom.: 1

Bravo AF: 0.00399

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000291 AC: 1

ESP6500EA AF: 0.00317 AC: 22

ExAC AF: 0.00110 AC: 93

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 28323911, 15170499, 15277425, 19515026, 10720084, 24097065, 10545531, 10545530, 26669242) -

Maturity onset diabetes mellitus in young Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2022	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. -
Likely pathogenic, criteria provided, single submitter	research	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	Dec 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 10, 2023	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 09, 2021	The p.Asp76Asn variant in the PDX1 gene has been classified as benign because it has been identified in 0.49% (336/68440) of Northern European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Maturity-onset diabetes of the young type 4 Benign:1 Other:1

not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp76Asn variant in PDX1 (sometimes called IPF1) has been reported in at least 32 individuals with Maturity-Onset Diabetes of the Young (PMID: 15277425, 10545531, 10545530, 17592437), and has been identified in 0.4909% (336/68440) of European (non-Finnish) chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852783). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. However, this variant does not segregate with disease in many families, including sibling pairs (PMID: 10545531, 15277425). This variant has also been reported as a benign variant, likely benign variant, VUS, likely pathogenic variant, and risk factor for diabetes in ClinVar (Variation ID: 8859). In vitro functional studies provide some evidence that the p.Asp76Asn variant may slightly impact protein function, but this evidence is not conclusive (PMID: 10545531). These types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for Maturity-Onset Diabetes of the Young in an autosomal dominant manner based on a higher than expected frequency in control cohorts and nonsegregation with MODY. ACMG/AMP Criteria applied: BS2, BS4, BP4 (Richards 2015). -

Diabetes mellitus type 2, susceptibility to Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Nov 01, 1999

- -

Type 2 diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 10, 2023

- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 12, 2018

ACMG criteria: BS2 (cases=controls in PMID 17592437, 21569088), BS1 (0.4% MAF in gnomAD)= benign; REVEL 0.245 +BP4/4 predictors + PP3/6 predictors: conflicting evidence, not using) OMIM suggests that it is a susceptability factor for T2DM -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.14	T
Polyphen		0.48	P
Vest4		0.43
MVP		0.87
MPC		1.1
ClinPred		0.019	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.55

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: rs137852783; hg19: chr13-28494501; COSMIC: COSV105828488; COSMIC: COSV105828488;