rs137852787

Variant names:

• chr13-27924519-G-A
• rs137852787
• NM_000209.4:c.670G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-27924519-G-A
• chr13-27924519-G-C

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.670G>A​(p.Glu224Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000508 in 1,607,848 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E224E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (7 hom.)
• Consequence: PDX1 NM_000209.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 6.23
• Publications: 19 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=0.008775234).
• BP6: Variant 13-27924519-G-A is Benign according to our data. Variant chr13-27924519-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8863.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000315 (48/152284) while in subpopulation SAS AF = 0.00972 (47/4834). AF 95% confidence interval is 0.00751. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.670G>A	p.Glu224Lys	missense	Exon 2 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.670G>A	p.Glu224Lys	missense	Exon 2 of 2	ENSP00000370421.4

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00992

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00129 AC: 304 AN: 236358 AF XY: 0.00175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000688

GnomAD4 exome AF: 0.000528 AC: 769 AN: 1455564 Hom.: 7 Cov.: 31 AF XY: 0.000752 AC XY: 544 AN XY: 723848

African (AFR) AF: 0.0000300 AC: 1 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00851 AC: 731 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52206

Middle Eastern (MID) AF: 0.000226 AC: 1 AN: 4432

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110022

Other (OTH) AF: 0.000600 AC: 36 AN: 60000

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00972 AC: 47 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.00151 AC: 182

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	1	1	Maturity-onset diabetes of the young type 4 (2)
-	1	1	not provided (2)
-	2	-	Type 2 diabetes mellitus (2)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Monogenic diabetes (1)
-	1	-	Type 2 diabetes mellitus;C1833382:Maturity-onset diabetes of the young type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.049	D
Polyphen		0.69	P
Vest4		0.24
MutPred		0.65		Gain of catalytic residue at V220 (P = 0.001)
MVP		0.97
MPC		1.3
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.48
gMVP		0.65
Mutation Taster		=89/11	polymorphism

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: rs137852787; hg19: chr13-28498656; COSMIC: COSV107491587;