rs199644078

Variant names:

• chr13-27924565-C-A
• rs199644078
• NM_000209.4:c.716C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-27924565-C-A
• chr13-27924565-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.716C>A​(p.Pro239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,502,110 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P239L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (28 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.961
• Publications: 12 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: 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=0.0057828426).
• BP6: Variant 13-27924565-C-A is Benign according to our data. Variant chr13-27924565-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129881.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0094 (1431/152158) while in subpopulation AFR AF = 0.0235 (975/41532). AF 95% confidence interval is 0.0223. There are 18 homozygotes in GnomAd4. There are 682 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.716C>A	p.Pro239Gln	missense	Exon 2 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.716C>A	p.Pro239Gln	missense	Exon 2 of 2	ENSP00000370421.4	P52945

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1417 AN: 152050 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00597 AC: 651 AN: 109026 AF XY: 0.00599

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00555

Gnomad EAS exome AF: 0.00126

Gnomad FIN exome AF: 0.00998

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00443 AC: 5977 AN: 1349952 Hom.: 28 Cov.: 31 AF XY: 0.00448 AC XY: 2973 AN XY: 664292

African (AFR) AF: 0.0252 AC: 714 AN: 28290

American (AMR) AF: 0.00322 AC: 99 AN: 30736

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 72 AN: 22338

East Asian (EAS) AF: 0.000566 AC: 19 AN: 33570

South Asian (SAS) AF: 0.00604 AC: 434 AN: 71804

European-Finnish (FIN) AF: 0.00776 AC: 321 AN: 41354

Middle Eastern (MID) AF: 0.00284 AC: 11 AN: 3868

European-Non Finnish (NFE) AF: 0.00378 AC: 4014 AN: 1062078

Other (OTH) AF: 0.00524 AC: 293 AN: 55914

GnomAD4 genome AF: 0.00940 AC: 1431 AN: 152158 Hom.: 18 Cov.: 32 AF XY: 0.00917 AC XY: 682 AN XY: 74396

African (AFR) AF: 0.0235 AC: 975 AN: 41532

American (AMR) AF: 0.00575 AC: 88 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5154

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.00416 AC: 44 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00365 AC: 248 AN: 67976

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00678 Hom.: 2

Bravo AF: 0.0103

ESP6500AA AF: 0.0127 AC: 48

ESP6500EA AF: 0.00202 AC: 15

ExAC AF: 0.00438 AC: 423

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Maturity-onset diabetes of the young (1)
-	-	1	Maturity-onset diabetes of the young type 4 (1)
-	-	1	Monogenic diabetes (1)
-	1	-	Pancreatic hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.96
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.22
Sift	Uncertain	0.015	D
Sift4G	Benign	0.19	T
Polyphen		0.024	B
Vest4		0.24
MVP		0.60
MPC		1.0
ClinPred		0.0094	T
GERP RS		2.8
Varity_R		0.079
gMVP		0.58
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199644078; hg19: chr13-28498702;