rs192902098

Variant names:

• chr13-27920235-C-A
• rs192902098
• NM_000209.4:c.97C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-27920235-C-A
• chr13-27920235-C-G
• chr13-27920235-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000209.4(PDX1):​c.97C>A​(p.Pro33Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,548,334 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (15 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 5.58
• Publications: 38 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 -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.26592 (below the threshold of 3.09). Trascript score misZ: -1.1553 (below the threshold of 3.09). GenCC associations: The gene is linked to pancreatic agenesis 1, monogenic diabetes, pancreatic agenesis, maturity-onset diabetes of the young, permanent neonatal diabetes mellitus, maturity-onset diabetes of the young type 4.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03478363).
• BP6: Variant 13-27920235-C-A is Benign according to our data. Variant chr13-27920235-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36414.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0018 (274/152286) while in subpopulation AMR AF = 0.0049 (75/15308). AF 95% confidence interval is 0.00401. There are 2 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.97C>A	p.Pro33Thr	missense	Exon 1 of 2	NP_000200.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDX1	ENST00000381033.5	TSL:1 MANE Select	c.97C>A	p.Pro33Thr	missense	Exon 1 of 2	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00256 AC: 364 AN: 142222 AF XY: 0.00289

Gnomad AFR exome AF: 0.000300

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000857

Gnomad EAS exome AF: 0.000570

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00201 AC: 2808 AN: 1396048 Hom.: 15 Cov.: 33 AF XY: 0.00212 AC XY: 1462 AN XY: 688488

African (AFR) AF: 0.000477 AC: 15 AN: 31440

American (AMR) AF: 0.00264 AC: 94 AN: 35628

Ashkenazi Jewish (ASJ) AF: 0.000438 AC: 11 AN: 25122

East Asian (EAS) AF: 0.000140 AC: 5 AN: 35676

South Asian (SAS) AF: 0.00607 AC: 480 AN: 79110

European-Finnish (FIN) AF: 0.00136 AC: 65 AN: 47714

Middle Eastern (MID) AF: 0.00435 AC: 24 AN: 5520

European-Non Finnish (NFE) AF: 0.00184 AC: 1982 AN: 1077984

Other (OTH) AF: 0.00228 AC: 132 AN: 57854

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74464

African (AFR) AF: 0.000481 AC: 20 AN: 41596

American (AMR) AF: 0.00490 AC: 75 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5160

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00198

ExAC AF: 0.00141 AC: 90

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Maturity-onset diabetes of the young type 4 (2)
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Monogenic diabetes (1)
-	1	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.035	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		2.1
ClinPred		0.044	T
GERP RS		5.5
PromoterAI		0.00040	Neutral
Varity_R		0.74
gMVP		0.70
Mutation Taster		=15/85	disease causing

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: rs192902098; hg19: chr13-28494372; COSMIC: COSV66847219; COSMIC: COSV66847219;