chr13-27920195-G-A

Variant names:

• chr13-27920195-G-A
• rs1242500017
• NM_000209.4:c.57G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_000209.4(PDX1):​c.57G>A​(p.Ala19Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,397,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A19A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PDX1 NM_000209.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.50
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-3.5 with no splicing effect.

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.57G>A	p.Ala19Ala	synonymous	Exon 1 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.57G>A	p.Ala19Ala	synonymous	Exon 1 of 2	ENSP00000370421.4	P52945

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000137 AC: 2 AN: 145644 AF XY: 0.0000254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000929

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1397476 Hom.: 0 Cov.: 33 AF XY: 0.0000247 AC XY: 17 AN XY: 689296

African (AFR) AF: 0.00 AC: 0 AN: 31554

American (AMR) AF: 0.00 AC: 0 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25134

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35742

South Asian (SAS) AF: 0.00 AC: 0 AN: 79208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.0000269 AC: 29 AN: 1078642

Other (OTH) AF: 0.00 AC: 0 AN: 57960

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.7
DANN	Benign	0.94
PhyloP100		-3.5
PromoterAI		0.19	Neutral

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: rs1242500017; hg19: chr13-28494332;