rs141133579

Positions:

chr1-160280067-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002857.4(PEX19):c.771+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,613,042 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 29 hom. )

Consequence

PEX19
NM_002857.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.0002355

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.323

Variant links:

Genes affected

PEX19 (HGNC:9713): (peroxisomal biogenesis factor 19) This gene is necessary for early peroxisomal biogenesis. It acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. These disorders have at least 14 complementation groups, with more than one phenotype being observed for some complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of Zellweger syndrome (ZWS), as well as peroxisome biogenesis disorder complementation group 14 (PBD-CG14), which is also known as PBD-CGJ. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

PEX19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 1-160280067-T-C is Benign according to our data. Variant chr1-160280067-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 282033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00412 (627/152306) while in subpopulation NFE AF= 0.00562 (382/68006). AF 95% confidence interval is 0.00515. There are 5 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PEX19	NM_002857.4 linkuse as main transcript	c.771+3A>G	splice_donor_region_variant, intron_variant	ENST00000368072.10
PEX19	NM_001193644.1 linkuse as main transcript	c.771+3A>G	splice_donor_region_variant, intron_variant
PEX19	NR_036492.2 linkuse as main transcript	n.670+3A>G	splice_donor_region_variant, intron_variant, non_coding_transcript_variant
PEX19	NR_036493.2 linkuse as main transcript	n.694+3A>G	splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX19	ENST00000368072.10 linkuse as main transcript	c.771+3A>G		splice_donor_region_variant, intron_variant		1	NM_002857.4	P1	P40855-1

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

627

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00562

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00471

AC:

1182

AN:

250936

Hom.:

AF XY:

0.00491

AC XY:

666

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.00623

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00569

AC:

8313

AN:

1460736

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

4162

AN XY:

726730

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00128

Gnomad4 FIN exome

AF:

0.0161

Gnomad4 NFE exome

AF:

0.00626

Gnomad4 OTH exome

AF:

0.00409

GnomAD4 genome

AF:

0.00412

AC:

627

AN:

152306

Hom.:

Cov.:

AF XY:

0.00444

AC XY:

331

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0152

Gnomad4 NFE

AF:

0.00562

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00519

Hom.:

Bravo

AF:

0.00327

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PEX19: BP4, BS2 -

Peroxisome biogenesis disorder 12A (Zellweger)

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 27, 2015

- -

PEX19-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.1

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.018

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

Publications

LitVar

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

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