1-160277327-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002857.4(PEX19):c.*2224G>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 0.000546 in 456,078 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (6 hom.)
• Consequence: PEX19 NM_002857.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000282 (43/152326) while in subpopulation SAS AF= 0.00207 (10/4830). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX19	NM_002857.4	c.*2224G>T		3_prime_UTR_variant	8/8	ENST00000368072.10
PEX19	NM_001193644.1	c.*2232G>T		3_prime_UTR_variant	8/8
PEX19	NR_036492.2	n.3023G>T		non_coding_transcript_exon_variant	7/7
PEX19	NR_036493.2	n.3047G>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX19	ENST00000368072.10	c.*2224G>T		3_prime_UTR_variant	8/8	1	NM_002857.4	P1
PEX19	ENST00000472750.5	c.*2891G>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
PEX19	ENST00000467711.5	n.180G>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000468 AC: 60 AN: 128104 Hom.: 0 AF XY: 0.000556 AC XY: 39 AN XY: 70158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000452

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000752

GnomAD4 exome AF: 0.000678 AC: 206 AN: 303752 Hom.: 6 Cov.: 0 AF XY: 0.000879 AC XY: 152 AN XY: 172978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000513

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000230

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 12A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	6.1
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs573966291; hg19: chr1-160247117;