rs797045885

Variant names:

• chr13-27920423-G-A
• rs797045885
• NM_000209.4:c.285G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-27920423-G-A
• chr13-27920423-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000209.4(PDX1):​c.285G>A​(p.Pro95Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PDX1 NM_000209.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.840
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 13-27920423-G-A is Benign according to our data. Variant chr13-27920423-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211894.
• BP7: Synonymous conserved (PhyloP=0.84 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDX1	NM_000209.4	MANE Select	c.285G>A	p.Pro95Pro	synonymous	Exon 1 of 2	NP_000200.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDX1	ENST00000381033.5	TSL:1 MANE Select	c.285G>A	p.Pro95Pro	synonymous	Exon 1 of 2	ENSP00000370421.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416012 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 700186

African (AFR) AF: 0.00 AC: 0 AN: 32544

American (AMR) AF: 0.00 AC: 0 AN: 37780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25300

East Asian (EAS) AF: 0.00 AC: 0 AN: 37532

South Asian (SAS) AF: 0.00 AC: 0 AN: 81084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5080

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088968

Other (OTH) AF: 0.0000171 AC: 1 AN: 58576

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		0.84
PromoterAI		0.0078	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: rs797045885; hg19: chr13-28494560; COSMIC: COSV66847013; COSMIC: COSV66847013;