1-160277134-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002857.4(PEX19):c.*2417C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 453,938 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (51 hom., cov: 32)
  • Exomes 𝑓: 0.028 (160 hom.)
• Consequence: PEX19 NM_002857.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.256

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-160277134-G-A is Benign according to our data. Variant chr1-160277134-G-A is described in ClinVar as [Benign]. Clinvar id is 875945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0255 (3875/151836) while in subpopulation NFE AF= 0.0345 (2347/67982). AF 95% confidence interval is 0.0334. There are 51 homozygotes in gnomad4. There are 1801 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX19	NM_002857.4	c.*2417C>T		3_prime_UTR_variant	8/8	ENST00000368072.10
PEX19	NM_001193644.1	c.*2425C>T		3_prime_UTR_variant	8/8
PEX19	NR_036492.2	n.3216C>T		non_coding_transcript_exon_variant	7/7
PEX19	NR_036493.2	n.3240C>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX19	ENST00000368072.10	c.*2417C>T		3_prime_UTR_variant	8/8	1	NM_002857.4	P1
PEX19	ENST00000472750.5	c.*3084C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	1

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3874 AN: 151734 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0252 AC: 3243 AN: 128854 Hom.: 55 AF XY: 0.0267 AC XY: 1882 AN XY: 70528

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0327

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0284 AC: 8571 AN: 302102 Hom.: 160 Cov.: 0 AF XY: 0.0294 AC XY: 5060 AN XY: 172164

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0322

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0326

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0255 AC: 3875 AN: 151836 Hom.: 51 Cov.: 32 AF XY: 0.0243 AC XY: 1801 AN XY: 74156

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.0204

Gnomad4 NFE AF: 0.0345

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0307 Hom.: 18

Bravo AF: 0.0249

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 12A (Zellweger) Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.4
Dann	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs193290301; hg19: chr1-160246924;