Genetic Variant PDX1:c.-29_-23delCTCCCGG (chr13-27920088-ACTCCCGG-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000209.4(PDX1):c.-29_-23delCTCCCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,546,280 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

PDX1
NM_000209.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.941

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant 13-27920088-ACTCCCGG-A is Benign according to our data. Variant chr13-27920088-ACTCCCGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 422562.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000494 (75/151748) while in subpopulation NFE AF= 0.000619 (42/67886). AF 95% confidence interval is 0.00047. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDX1	NM_000209.4 link	c.-29_-23delCTCCCGG		5_prime_UTR_variant	Exon 1 of 2	ENST00000381033.5	NP_000200.1	P52945

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDX1	ENST00000381033 link	c.-29_-23delCTCCCGG		5_prime_UTR_variant	Exon 1 of 2	1	NM_000209.4	ENSP00000370421.4		P52945

Frequencies

GnomAD3 genomes

AF:

0.000481

AC:

AN:

151636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000509

Gnomad AMI

AF:

0.00221

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000619

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000465

AC:

AN:

142004

Hom.:

AF XY:

0.000351

AC XY:

AN XY:

76988

show subpopulations

Gnomad AFR exome

AF:

0.000322

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.000122

Gnomad EAS exome

AF:

0.000379

Gnomad SAS exome

AF:

0.000179

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000864

Gnomad OTH exome

AF:

0.000722

GnomAD4 exome

AF:

0.000594

AC:

829

AN:

1394532

Hom.:

AF XY:

0.000587

AC XY:

404

AN XY:

687796

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.000279

Gnomad4 EAS exome

AF:

0.000673

Gnomad4 SAS exome

AF:

0.000480

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000617

Gnomad4 OTH exome

AF:

0.000796

GnomAD4 genome

AF:

0.000494

AC:

AN:

151748

Hom.:

Cov.:

AF XY:

0.000486

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.000556

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000619

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000620

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

13-27920088-ACTCCCGGCTCCCGG-ACTCCCGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over