1-160280067-T-C

Position:

• chr1-160280067-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000368072.10(PEX19):​c.771+3A>G variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 ENST00000368072.10 splice_region, intron
• Scores: Splicing: ADA: 0.0002355
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.323

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]

ENSG00000258465 (HGNC:):

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX19	NM_002857.4	c.771+3A>G		splice_region_variant, intron_variant		ENST00000368072.10	NP_002848.1
PEX19	NM_001193644.1	c.771+3A>G		splice_region_variant, intron_variant			NP_001180573.1
PEX19	NR_036492.2	n.670+3A>G		splice_region_variant, intron_variant
PEX19	NR_036493.2	n.694+3A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX19	ENST00000368072.10	c.771+3A>G		splice_region_variant, intron_variant		1	NM_002857.4	ENSP00000357051.5
ENSG00000258465	ENST00000485079.1	c.381+3A>G		splice_region_variant, intron_variant		3		ENSP00000450870.1

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152188 Hom.: 5 Cov.: 32

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.: 3 AF XY: 0.00491 AC XY: 666 AN XY: 135618

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.: 29 Cov.: 32 AF XY: 0.00573 AC XY: 4162 AN XY: 726730

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.: 5 Cov.: 32 AF XY: 0.00444 AC XY: 331 AN XY: 74478

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.: 2

Bravo AF: 0.00327

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 27, 2015

- -

PEX19-related disorder Benign:1

Benign, no assertion criteria provided

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

Other links and lift over

dbSNP: rs141133579; hg19: chr1-160249857;